Bicyclic pyridinones

ABSTRACT

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I 
                         
as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

This application is a Non-Provisional application under 35 U.S.C. 119(e)which claims the benefit of U.S. Patent Application No. 61/599,022 filedon Feb. 15, 2012 which claims benefit of U.S. Patent Application No.61/470,076 filed on Mar. 31, 2011.

The present invention relates to the treatment of Alzheimer's diseaseand other neurodegenerative and/or neurological disorders in mammals,including humans. This invention also relates to the modulation, inmammals, including humans, of the production of A-beta peptides that cancontribute to the formation of neurological deposits of amyloid protein.More particularly, this invention relates to novel bicyclic pyridinonecompounds useful for the treatment of neurodegenerative and/orneurological disorders, such as Alzheimer's disease and Down's Syndrome,related to A-beta peptide production.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (AD), cerebral amyloid angiopathy (CM) andprion-mediated diseases (see, e.g., Haan et al., Clin. Neurol.Neurosurg. 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci. 1989,94:1-28). AD affects nearly half of all people past the age of 85, themost rapidly growing portion of the United States population. As such,the number of AD patients in the United States is expected to increasefrom about 4 million to about 14 million by the middle of the nextcentury.

The present invention relates to a group of brain-penetrable γ-secretasemodulators useful as γ-secretase modulators for the treatment ofneurodegenerative and/or neurological disorders that are related toA-beta peptide production, such as Alzheimer's disease and Down'sSyndrome. (see Ann. Rep. Med. Chem. 2007, Olsen et al., 42: 27-47).

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I, includingthe pharmaceutically acceptable salts thereof,

wherein:

X is a 5- to 14-membered heteroaryl containing 1-3 heteroatoms;

R¹ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₂₋₆alkenyl orC₂₋₆alkynyl; wherein said alkyl, cycloalkyl, alkenyl or alkynyl may beoptionally and independently substituted with one to three of fluoro,cyano, —CF₃, hydroxyl, or C₁₋₆alkoxy groups;

R^(2a) and R^(2b) for each occurrence are each independently hydrogen,fluoro, cyano, —CF₃, C₁₋₆alkyl, C₃₋₆cycloalkyl, (C₄₋₁₀)bicycloalkyl,C₂₋₆alkenyl, C₂₋₆alkylidene, or C₂₋₆alkynyl; wherein said alkyl,cycloalkyl, bicycloalkyl, alkenyl, alkylidene or alkynyl may beoptionally and independently substituted with cyano, C₁₋₃alkyl or one tothree fluoro; or R^(2a) and R^(2b) together with the carbon to whichthey are bonded form a 3- to 5-membered cycloalkyl optionallysubstituted with one to three R⁸;

R³ is —(C(R¹¹)₂)_(t)—(C₆₋₁₀aryl) or —(C(R¹¹)₂)_(t)-(5- to 14-memberedheteroaryl); wherein said aryl or heteroaryl moieties may be optionallyindependently substituted with one to five R¹⁰;

R^(4a) and R^(4b) are each independently hydrogen, —CF₃, or C₁₋₆alkyl,wherein said alkyl is optionally substituted with one to three —CF₃,cyano or fluoro; or R^(4a) and R^(4b) together with the carbon to whichthey are bonded form a 3- to 5-membered cycloalkyl, wherein saidcycloalkyl is optionally substituted with one to three of —CF₃, cyano,fluoro or C₁₋₆alkyl;

R^(5a) and R^(5b) for each occurrence are each independently hydrogen,—CF₃, or C₁₋₆alkyl, wherein said alkyl is optionally substituted withone to three —CF₃, cyano or fluoro; or R^(5a) and R^(5b) together withthe carbon to which they are bonded form a 3- to 5-membered cycloalkyl,wherein said cycloalkyl is optionally substituted with one to three—CF₃, cyano, fluoro or C₁₋₆alkyl;

R⁶, R⁷ and R⁸ are independently hydrogen, —CF₃, cyano, halogen,C₁₋₆alkyl or —OR⁹; provided that R⁶ and R⁷ cannot both be —OH;

R⁹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆alkenyl or C₃₋₆alkynyl;wherein said alkyl, cycloalkyl, alkenyl or alkynyl may be optionally andindependently substituted with cyano, or one to three fluoro;

each R¹⁰ is independently hydrogen, halogen, cyano, —CF₃, C₁₋₆alkyl,—(C(R¹¹)₂)_(m)—(C₃₋₆cycloalkyl), —(C(R¹¹)₂)_(m)—((C₄₋₁₀)bicycloalkyl),—(C(R¹¹)₂)_(m)-(4- to 10-membered heterocycloalkyl),—(C(R¹¹)₂)_(m)—(C₆₋₁₀aryl), —(C(R¹¹)₂)_(m)-(5- to 10-memberedheteroaryl), —(C(R¹¹)₂)_(m)—OR¹², —C(O)R¹³, —SF₅ or —Si(CH₃)₃; whereinsaid alkyl, cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl orheteroaryl moieties may be optionally and independently substituted withone to three R¹⁴;

each R¹¹ is independently hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₄cycloalkyl, fluoro, —CF₃, —CHF₂ or —OR¹²; wherein said alkyl,alkenyl, alkynyl or cycloalkyl moieties may be optionally independentlysubstituted with one to three fluoro or cyano;

each R¹² is independently hydrogen, C₁₋₆alkyl, —CF₃,—(C(R¹⁴)₂)_(n)—(C₃₋₆cycloalkyl), —(C(R¹⁴)₂)_(n)-(4- to 10-memberedheterocycloalkyl), —(C(R¹⁴)₂)_(n)—(C₆₋₁₀aryl) or —(C(R¹⁴)₂)_(n)-(5- to10-membered heteroaryl); wherein said alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl moieties may be optionallyindependently substituted with one to three R¹⁶;

each R¹³ is independently C₁₋₆alkyl, —(C(R¹⁶)₂)_(p)—(C₃₋₆cycloalkyl),—(C(R¹⁶)₂)_(p)-(4- to 10-membered heterocycloalkyl),—(C(R¹⁶)₂)_(p)—(C₆₋₁₀aryl) or —(C(R¹⁶)₂)_(p)-(5- to 10-memberedheteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl moieties may be optionally independently substituted with oneto three R¹⁶;

each R¹⁴ is independently hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,halogen, cyano, —CF₃, —CHF₂, —OR⁹ or —OCF₃;

R¹⁶ is independently hydrogen, —CF₃, cyano, halogen, C₁₋₆alkyl or —OR⁹;wherein said alkyl moiety may be optionally substituted with one tothree R¹⁷;

R¹⁷ is independently hydrogen, hydroxyl, —CF₃, cyano, fluoro,C₂₋₆alkenyl or C₂₋₆alkynyl; wherein said alkenyl or alkynyl moiety maybe optionally substituted with one to three hydrogen, fluoro orC₁₋₆alkyl; and

each t, m, n or p is an integer independently selected from 0, 1, 2, 3,and 4;

z is an integer selected from 1 and 2;

y is an integer selected from 1, 2, 3 and 4

and pharmaceutically acceptable salts thereof.

In one embodiment, X is imidazolyl, pyrazolyl, isothiazolyl, thiazolyl,isoxazolyl, oxazolyl or pyridyl. In a preferred embodiment, X isimidazolyl.

In another embodiment, R¹ is C₁₋₆alkyl. In a preferred embodiment, R¹ ismethyl, y is two or three and z is 1.

In one embodiment, R³ is aryl or heteroraryl. In a preferred embodiment,R³ is phenyl, naphthalene, 2,3-dihydro-1H-indene, quinoline,isoquinoline, pyrazole, benzo[b]furan, 2,3-dihydrobenzofuran,1,2-benzisothiazole, 1,3-benzothiazole, benzofuro[3,2-c]pyridine,pyridine, carbazole, benzo[d]isoxazole, benzocyclobutane,1,2,3,4-tetrahydronaphthalene, dibenzo[b,d]thiophene, dibenzo[b,d]furanor cinnoline.

In one embodiment, R¹⁰ is independently hydrogen, halogen, cyano, —CF₃,C₁₋₆alkyl, (C₄₋₁₀)bicycloalkyl, —(C(R¹¹)₂)_(m)—(C₃₋₆cycloalkyl),—(C(R¹¹)₂)_(m)-(4- to 10-membered heterocycloalkyl),—(C(R¹¹)₂)_(m)—(C₆₋₁₀aryl), —(C(R¹¹)₂)_(m)-(5- to 10-memberedheteroaryl), —(C(R¹¹)₂)_(m)—OR¹² or —C(O)R¹³; wherein the alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moieties may beindependently substituted with one to three R¹⁴. In a preferredembodiment, R¹⁰ is hydrogen, chloro, fluoro, bromo, cyano, —CF₃, —OCF₃,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl,cyclobutyl, bicycloalkyl, hydroxyl, methoxy, pyrazole, isothiazole,thiazole, 1,3,4-thiadiazole, isoxazole, oxazole, pyridine, piperidine,benzofuran, benzo[d][1,3]dioxole, tetrahydropyrane or phenyl; whereinsaid C₁₋₆alkyl, bicycloalkyl, cycloalkyl, heterocycloalkyl, heteroarylor aryl moieties may be optionally independently substituted with one tothree R¹⁴.

In a preferred embodiment, R³ is phenyl, naphthalene,2,3-dihydro-1H-indene, quinoline, isoquinoline, pyrazole, benzo[b]furan,2,3-dihydrobenzofuran, 1,2-benzisothiazole, 1,3-benzothiazole,benzofuro[3,2-c]pyridine, pyridine, carbazole, benzo[d]isoxazole,1,2,3,4-tetrahydronaphthalene, dibenzo[b,d]thiophene, dibenzo[b,d]furan,benzoyclobutane or cinnoline;

R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R⁷ and R⁸ are each independentlyhydrogen or C₁₋₆alkyl;

R¹⁴ is independently hydrogen, C₁₋₆alkyl, chloro, bromo or fluoro, —CF₃,—CHF₂ or —OR⁹;

and R¹⁷ is independently hydrogen or —CF₃ or phenyl; wherein said phenyland C₁₋₆alkyl moieties may be independently substituted with one tothree hydrogen or halogen;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention also relates to each of the individualcompounds described as Examples 1-116 in the Examples section of thesubject application, (including the free bases or pharmaceuticallyacceptable salts thereof).

In another embodiment the invention relates to a preferred compoundselected from the group consisting of:

7-(4-methyl-1H-imidazol-1-yl)-2-(2-{2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-fluoro-2-(trifluoromethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-(2-{2-[3-(trifluoromethyl)isoxazol-5-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[4-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-7-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[2-(3,3-difluorocyclobutyl)-4-fluorophenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-(2-{[2-(trifluoromethyl)-1,3-benzothiazol-7-yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,trifluoroacetate salt;

7-(4-methyl-1H-imidazol-1-yl)-2-(2-{2-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-fluoro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[2-(bicyclo[1.1.1]pent-1-yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(2S)-1-[4-chloro-2-(trifluoromethyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-1,3-benzodioxol-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;and

2-{2-[2-(bicyclo[1.1.1]pent-1-yl)-4-chlorophenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione

or a pharmaceutically acceptable salt of any of the above.

Yet another aspect of this invention is directed to a method fortreating conditions or diseases of the central nervous system identifiedto have enhanced gamma secretase activity, such as Niemann Pick type C;neurological disorder (such as migraine; epilepsy; Alzheimer's disease;Parkinson's disease; brain injury; stroke; cerebrovascular diseases(including cerebral arteriosclerosis, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, and brain hypoxia-ischemia); cognitivedisorders (including amnesia, senile dementia, HIV associated dementia,Alzheimer's disease, Huntington's disease, Lewy body dementia, vasculardementia, drug related dementia, tardive dyskinesia, myoclonus,dystonia, delirium, Pick's disease, Creutzfeldt-Jacob disease, HIVdisease, Gilles de la Tourette's syndrome, epilepsy, muscular spasms anddisorders associated with muscular spasticity or weakness includingtremors, and mild cognitive impairment); mental deficiency (includingspasticity, Down syndrome and fragile X syndrome); sleep disorders(including hypersomnia, circadian rhythm sleep disorder, insomnia,parasomnia, and sleep deprivation) and psychiatric disorders (such asanxiety (including acute stress disorder, generalized anxiety disorder,social anxiety disorder, panic disorder, post-traumatic stress disorder,agoraphobia, and obsessive-compulsive disorder); factitious disorder(including acute hallucinatory mania); impulse control disorders(including compulsive gambling and intermittent explosive disorder);mood disorders (including bipolar I disorder, bipolar II disorder,mania, mixed affective state, major depression, chronic depression,seasonal depression, psychotic depression, seasonal depression,premenstrual syndrome (PMS) premenstrual dysphoric disorder (PDD), andpostpartum depression); psychomotor disorder; psychotic disorders(including schizophrenia, schizoaffective disorder, schizophreniform,and delusional disorder); drug dependence (including narcoticdependence, alcoholism, amphetamine dependence, cocaine addiction,nicotine dependence, and drug withdrawal syndrome); eating disorders(including anorexia, bulimia, binge eating disorder, hyperphagia,obesity, compulsive eating disorders and pagophagia); sexual dysfunctiondisorders, urinary incontinence; neuronal damage disorders (includingocular damage, retinopathy or macular degeneration of the eye, tinnitus,hearing impairment and loss, and brain edema) and pediatric psychiatricdisorders (including attention deficit disorder, attentiondeficit/hyperactive disorder, conduct disorder, and autism) in a mammal,preferably a human, comprising administering to said mammal atherapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof.

Compounds of Formula I may also be useful for improving memory (bothshort term and long term) and learning ability.

The text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic tool foridentifying many of the disorders described herein. The skilled artisanwill recognize that there are alternative nomenclatures, nosologies, andclassification systems for disorders described herein, including thoseas described in the DMS-IV and that terminology and classificationsystems evolve with medical scientific progress.

Preferred methods are for treating a neurological disorder (such asmigraine; epilepsy; Alzheimer's disease; Parkinson's disease; NiemannPick type C; brain injury; stroke; cerebrovascular disease; cognitivedisorder; sleep disorder) or a psychiatric disorder (such as anxiety;factitious disorder; impulse control disorder; mood disorder;psychomotor disorder; psychotic disorder; drug dependence; eatingdisorder; and pediatric psychiatric disorder) in a mammal, preferably ahuman, comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I or pharmaceuticallyacceptable salt thereof.

Also provided herein are compositions comprising a pharmaceuticallyeffective amount of one or more of the compounds described herein and apharmaceutically acceptable vehicle, carrier or excipient.

The present invention includes the use of a combination of a γ-secretasemodulator compound as provided in Formula I and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of Formula I or a pharmaceutically acceptable salt of thecompound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of Formula I, depending on the disease,disorder, or condition to be treated. Pharmaceutically active agentsthat may be used in combination with the compositions of the presentinvention include, without limitation:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride(ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigminesulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine(MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also knownas ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361,galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX),tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A;NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

(ii) amyloid-β (or fragments thereof), such as Aβ₁₋₁₅ conjugated to panHLA DR-binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24,AN-1792, Affitope AD-01, CAD106, and V-950;

(iii) antibodies to amyloid-β (or fragments thereof), such as ponezumab,solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan),ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanizedm266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those disclosed inInternational Patent Publication Nos WO04/032868, WO05/025616,WO06/036291, WO06/069081, WO06/118959, in US Patent Publication NosUS2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, inEuropean Patent Publication Nos EP0994728 and 1257584, and in U.S. Pat.No. 5,750,349;

(iv) amyloid-lowering or -inhibiting agents (including those that reduceamyloid production, accumulation and fibrillization) such as dimebon,davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin,anapsos, oxiracetam, pramiracetam, varenicline, nicergoline,colostrinin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics),E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2(Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and itsR-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen(FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofenlysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN),indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenacpotassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID),naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (ArcherPharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degradingenzyme (also known as insulysin), the gingko biloba extract EGb-761(ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate(FIBRILLEX, KIACTA), compound W (3,5-bis(4-nitrophenoxy)benzoic acid),NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)),scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR),simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACEinhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683,AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; GammaSecretase Modulators such as ELND-007; and RAGE (receptor for advancedglycation end-products) inhibitors, such as TTP488 (Transtech) andTTP4000 (Transtech), and those disclosed in U.S. Pat. No. 7,285,293,including PTI-777;

(v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV,TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa(ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine(also known as neosynephrine), methoxamine, cirazoline, guanfacine(INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, andarmodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blocking agents (beta blockers), such ascarteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE),oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL),sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC),acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate(LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN),butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP),butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE),diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine,atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolaminemethylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT,DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL,OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine,imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL),oxcarbazepine (TRILEPTAL), phenyloin sodium (PHENYTEK), fosphenyloin(CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin(NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid(DEPAKENE), valproate sodium (DEPACON), 1-benzyl-5-bromouracil,progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022,retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496;Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE),haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate(DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazinedecanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO),asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN),perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE),ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone(RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA),quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON),blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine(ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN),felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT,PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP),nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS),lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil(CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone,tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

(xii) central nervous system stimulants, such as atomoxetine,reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine,pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethylline(CAPTAGON), pipradol (MERETRAN), deanol (also known asdimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidatehydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine(alone or in combination with other CNS stimulants, e.g. ADDERALL(amphetamine aspartate, amphetamine sulfate, dextroamphetaminesaccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate(DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine(VYVANSE), and benzphetamine (DIDREX);

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE),prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PREDFORTE), prednisolone sodum phosphate (ORAPRED ODT), methylprednisolone(MEDROL); methylprednisolone acetate (DEPO-MEDROL), andmethylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN),bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine,dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN),terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL),pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine(NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox andsarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine,fluphenazine, haloperidol, loxzpine, resperidone, thioridazine,thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE),7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN),domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A,SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide,nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) andits decanoate ester DBL-583, and amineptine;

(xvii) gamma-amino-butyric acid (GABA) receptor agonists, such asbaclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL),progabide (GABRENE), and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant,S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852,JNJ-17216498, HPP-404, SAR-110894,trans-3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanecarboxylic acid ethylamide (PF-3654746 and those disclosed in US PatentPublication Nos US2005-0043354, US2005-0267095, US2005-0256135,US2008-0096955, US2007-1079175, and US2008-0176925; International PatentPublication Nos WO2006/136924, WO2007/063385, WO2007/069053,WO2007/088450, WO2007/099423, WO2007/105053, WO2007/138431, andWO2007/088462; and U.S. Pat. No. 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known ascopolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic proteinpeptide), dimethyl fumarate, fingolimod (also known as FTY720),roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 andSAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab(RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab(TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX),mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT),mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN),mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN),chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX),alpha-fetoprotein, etanercept (ENBREL), and4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2′-bi-1H-pyrrole(also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) andinterferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combinationwith a DOPA decarboxylase inhibitor (e.g. carbidopa (SINEMET, CARBILEV,PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa,difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate(CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol,dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097,himantane, idantadol, ipenoxazone, L-701252 (Merck), lancicemine,levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone,(DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine(STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth),ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel(CERESOTAT), gavestinel, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM),selegiline hydrochloride (l-deprenyl, ELDEPRYL, ZELAPAR),dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine(PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide,isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (ChiesiFarmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane,desoxypeganine, harmine (also known as telepathine or banasterine),harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN,SUPIRDYL);

(xxv) muscarinic receptor (particularly M1 subtype) agonists, such ascevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE),itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck),L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethoniumbenzensulfonate, furtrethonium p-toluenesulfonate, McN-A-343,oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), andcarbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol,lamotrigine, perampanel, aniracetam, minaprime, viluzole2,3,4,9-tetrahydro-1H-carbazol-3-one oxime, desmoteplase, anatibant,astaxanthin, neuropeptide NAP (e.g. AL-108 and AL-208; both AllonTherapeutics), neurostrol, perampenel, ispronicline,bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyltartrate(also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA),lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE),arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known ascytidine 5′-diphosphocholine), edaravone (RADICUT), AEOL-10113 andAEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known asSA-450 and Msc-1), granulocyte-colony stimulating factor (also known asAX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod(VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220(17-β-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (alsoknown as oligotropin), pyridoxal 5′-phosphate (also known as MC-1),microplasmin, S-18986, piclozotan, NP031112, tacrolimus,L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine,AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes ofHealth), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory BiomedicalResearch), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropion,CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328(AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/MemoryPharmaceuticals), R4996 (also known as MEM63908; Roche/MemoryPharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such asatomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN),nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN,DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN),maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), andradaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including (a) PDE1 inhibitors(e.g. vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosedin U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors (e.g.erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and thosedescribed in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g.anagrelide, cilostazol, milrinone, olprinone, parogrelil, andpimobendan), (d) PDE4 inhibitors (e.g. apremilast, ibudilastroflumilast,rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known asRP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast,oglemilast (also known as GRC 3886), tetomilast (also known asOPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline(also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and(e) PDE5 inhibitors (e.g. sildenafil (VIAGRA, REVATIO), tadalafil(CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil,dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil,mirodenafil, DA-8159, and those disclosed in International PatentApplications WO2002/020521, WO2005/049616, WO2006/120552, WO2006/126081,WO2006/126082, WO2006/126083, and WO2007/122466), (f) PDE9 inhibitors(e.g. BAY 73-6691 (Bayer AG) and those disclosed in US PatentPublication Nos US2003/0195205, US2004/0220186, US2006/0111372,US2006/0106035, and U.S. Ser. No. 12/118,062 (filed May 9, 2008)), and(g) PDE10 inhibitor such as2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxymethyl]quinoline(PF-2545920), and SCH-1518291;

(xxx) quinolines, such as quinine (including its hydrochloride,dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine,sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), andamodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754,AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721,E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (alsoknown as LY-2434074), KMI-574, SCH-745966, Ac-rER(N²-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), andCA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163(Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009,L-685458 (Merck), ELAN-G, ELAN-Z,4-chloro-N-[2-ethyl-1(S)-(hydroxymethyl)butyl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT_(1A)) receptorantagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299,S(−)-UH-301, NAN 190, lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists,such as vabicaserin, and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists, suchas PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists,such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON,NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161,ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885,SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046,SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034(Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX),clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL),fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC),fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL,SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN),venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine,neuralstem and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basicfibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3),cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin,meteorin, and glial-derived neurotrophic factor (GDNF), and agents thatstimulate production of trophic factors, such as propentofylline,idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935,JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel,mibampator, selurampanel, GSK-729327, andN-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide;

and the like.

All patents, patent applications and references referred to herein arehereby incorporated by reference in their entirety.

Other features and advantages of this invention will be apparent fromthis specification and the appendent claims which describe theinvention.

DEFINITIONS

The term “alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen) containing from one to twenty carbon atoms; inone embodiment from one to twelve carbon atoms; in another embodiment,from one to ten carbon atoms; in another embodiment, from one to sixcarbon atoms; and in another embodiment, from one to four carbon atoms.Examples of such substituents include methyl, ethyl, propyl (includingn-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyland tert-butyl), pentyl, isoamyl, hexyl and the like. In some instances,the number of carbon atoms in a hydrocarbyl moiety (i.e., alkyl,cycloalkyl, etc.) is indicated by the prefix “C_(x-y),” wherein x is theminimum and y is the maximum number of carbon atoms in the substituent.Thus, for example, “C₁₋₆alkyl” refers to an alkyl substituent containingfrom 1 to 6 carbon atoms.

“Alkenyl” refers to an aliphatic hydrocarbon having at least onecarbon-carbon double bond, including straight chain, branched chain orcyclic groups having at least one carbon-carbon double bond. Preferably,it is a medium-size alkenyl having 2 to 6 carbon atoms. For example, asused herein, the term “C₂₋₆alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 5 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl. When the compounds ofthe invention contain a C₂₋₆alkenyl group, the compound may exist as thepure E (entgegen) form, the pure Z (zusammen) form, or any mixturethereof.

“Alkylidene” refers to a divalent group formed from an alkane by removalof two hydrogen atoms from the same carbon atom, the free valencies ofwhich are part of a double bond.

“Alkynyl” refers to an aliphatic hydrocarbon having at least onecarbon-carbon triple bond, including straight chain, branched chain orcyclic groups having at least one carbon-carbon triple bond. Preferably,it is a lower alkynyl having 2 to 6 carbon atoms. For example, as usedherein, the term “C₂₋₆alkynyl” is used herein to mean a straight orbranched hydrocarbon chain alkynyl radical as defined above having 2 to6 carbon atoms and one triple bond.

The term “cycloalkyl” refers to a carbocyclic substituent obtained byremoving a hydrogen from a saturated carbocyclic molecule and havingthree to fourteen carbon atoms. In one embodiment, a cycloalkylsubstituent has three to ten carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkyl” also includes substituents that are fused to aC₆-C₁₀ aromatic ring or to a 5- to 10-membered heteroaromatic ring,wherein a group having such a fused cycloalkyl group as a substituent isbound to a carbon atom of the cycloalkyl group. When such a fusedcycloalkyl group is substituted with one or more substituents, the oneor more substituents, unless otherwise specified, are each bound to acarbon atom of the cycloalkyl group. The fused C₆-C₁₀ aromatic ring or5- to 10-membered heteroaromatic ring may be optionally substituted withhalogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or ═O.

A cycloalkyl may be a single ring, which typically contains from 3 to 6ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. Alternatively, 2 or 3 rings may be fused together, such asbicyclodecanyl and decalinyl. The term “cycloalkyl” also includesbridged bicycloalkyl systems such as, but not limited to,bicyclo[2.2.1]heptane and bicyclo[1.1.1]pentane.

The term “aryl” refers to an aromatic substituent containing one ring ortwo or three fused rings. The aryl substituent may have six to eighteencarbon atoms. As an example, the aryl substituent may have six tofourteen carbon atoms. The term “aryl” may refer to substituents such asphenyl, naphthyl and anthracenyl. The term “aryl” also includessubstituents such as phenyl, naphthyl and anthracenyl that are fused toa C₄₋₁₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or to a4- to 10-membered heterocyclic ring, wherein a group having such a fusedaryl group as a substituent is bound to an aromatic carbon of the arylgroup. When such a fused aryl group is substituted with one or moresubstituents, the one or more substituents, unless otherwise specified,are each bound to an aromatic carbon of the fused aryl group. The fusedC₄₋₁₀ carbocyclic or 4- to 10-membered heterocyclic ring may beoptionally substituted with halogens, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or ═O.Examples of aryl groups include accordingly phenyl, naphthalenyl,tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl,isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (alsoknown as “phenalenyl”), and fluorenyl.

The term “hydrogen” refers to a hydrogen substituent, and may bedepicted as —H.

The term “hydroxy” or “hydroxyl” refers to —OH. When used in combinationwith another term(s), the prefix “hydroxy” indicates that thesubstituent to which the prefix is attached is substituted with one ormore hydroxy substituents. Compounds bearing a carbon to which one ormore hydroxy substituents are attached include, for example, alcohols,enols and phenol.

The term “cyano” (also referred to as “nitrile”) means —CN, which alsomay be depicted:

The term “halogen” refers to fluorine (which may be depicted as —F),chlorine (which may be depicted as —Cl), bromine (which may be depictedas —Br), or iodine (which may be depicted as —I). In one embodiment, thehalogen is chlorine. In another embodiment, the halogen is fluorine. Inanother embodiment, the halogen is bromine.

The term “heterocycloalkyl” refers to a substituent obtained by removinga hydrogen from a saturated or partially saturated ring structurecontaining a total of 4 to 14 ring atoms, wherein at least one of thering atoms is a heteroatom selected from oxygen, nitrogen, or sulfur.For example, as used herein, the term “4- to 10-memberedheterocycloalkyl” means the substituent is a single ring with 4 to 10total members. A heterocycloalkyl alternatively may comprise 2 or 3rings fused together, wherein at least one such ring contains aheteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In agroup that has a heterocycloalkyl substituent, the ring atom of theheterocycloalkyl substituent that is bound to the group may be the atleast one heteroatom, or it may be a ring carbon atom, where the ringcarbon atom may be in the same ring as the at least one heteroatom orwhere the ring carbon atom may be in a different ring from the at leastone heteroatom. Similarly, if the heterocycloalkyl substituent is inturn substituted with a group or substituent, the group or substituentmay be bound to the at least one heteroatom, or it may be bound to aring carbon atom, where the ring carbon atom may be in the same ring asthe at least one heteroatom or where the ring carbon atom may be in adifferent ring from the at least one heteroatom.

The term “heterocycloalkyl” also includes substituents that are fused toa C₆-C₁₀ aromatic ring or to a 5- to 10-membered heteroaromatic ring,wherein a group having such a fused heterocycloalkyl group as asubstituent is bound to a heteroatom of the heterocycloalkyl group or toa carbon atom of the heterocycloalkyl group. When such a fusedheterocycloalkyl group is substituted with one or more substituents, theone or more substituents, unless otherwise specified, are each bound toa heteroatom of the heterocycloalkyl group or to a carbon atom of theheterocycloalkyl group. The fused C₆-C₁₀ aromatic ring or 5- to10-membered heteroaromatic ring may be optionally substituted withhalogen, C₁₋₆alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆alkoxy, or ═O.

The term “heteroaryl” refers to an aromatic ring structure containingfrom 5 to 14 ring atoms in which at least one of the ring atoms is aheteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or3 fused rings. Examples of heteroaryl substituents include but are notlimited to: 6-membered ring substituents such as pyridyl, pyrazyl,pyrimidinyl, and pyridazinyl; 5-membered ring substituents such astriazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl; 6/5-membered fused ring substituents such asbenzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl; and 6/6-membered fused ring substituents suchas quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and1,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ringatom of the heteroaryl substituent that is bound to the group may be theat least one heteroatom, or it may be a ring carbon atom, where the ringcarbon atom may be in the same ring as the at least one heteroatom orwhere the ring carbon atom may be in a different ring from the at leastone heteroatom. Similarly, if the heteroaryl substituent is in turnsubstituted with a group or substituent, the group or substituent may bebound to the at least one heteroatom, or it may be bound to a ringcarbon atom, where the ring carbon atom may be in the same ring as theat least one heteroatom or where the ring carbon atom may be in adifferent ring from the at least one heteroatom. The term “heteroaryl”also includes pyridyl N-oxides and groups containing a pyridine N-oxidering.

In some instances, the number of atoms in a cyclic substituentcontaining one or more heteroatoms (i.e., heteroaryl orheterocycloalkyl) is indicated by the prefix “X- to Y-membered”, whereinX is the minimum and Y is the maximum number of atoms forming the cyclicmoiety of the substituent. Thus, for example, 5- to 8-memberedheterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8atoms, including one or more heteroatoms, in the cyclic moiety of theheterocycloalkyl.

Examples of single-ring heteroaryls and heterocycloalkyls include butare not limited to furanyl, dihydrofuranyl, tetrahydrofuranyl,thiophenyl (also known as “thiofuranyl”), dihydrothiophenyl,tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl,imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl,oxathiolyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,thiadiazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl,1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2,5-oxadiazolyl (alsoknown as “furazanyl”), or 1,3,4-oxadiazolyl), pyranyl (including1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as“azinyl”), piperidinyl, diazinyl (including pyridazinyl (also known as“1,2-diazinyl”), pyrimidinyl (also known as “1,3-diazinyl” or“pyrimidyl”), or pyrazinyl (also known as “1,4-diazinyl”)), piperazinyl,triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”),as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also knownas “1,2,3-triazinyl”)), morpholinyl, azepinyl, oxepinyl, thiepinyl, anddiazepinyl.

Examples of 2-fused-ring heteroaryls and heterocycloalkyls include butare not limited to indolizinyl, pyranopyrrolyl, 4H-quinolizinyl,purinyl, naphthyridinyl, pyridopyridinyl (includingpyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, orpyrido[4,3-b]pyridinyl), and pteridinyl, indolyl, isoindolyl,isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl,indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

Examples of 3-fused-ring heteroaryls or heterocycloalkyls include butare not limited to 5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline,4,5-dihydroimidazo[4,5,1-hi]indole,4,5,6,7-tetrahydroimidazo[4,5,1-jk][1]benzazepine, and dibenzofuranyl.

Other examples of fused-ring heteroaryls include but are not limited tobenzo-fused heteroaryls such as indolyl, isoindolyl (also known as“isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”),benzazinyl (including quinolinyl (also known as “1-benzazinyl”) orisoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl,quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (alsoknown as “1,2-benzodiazinyl”) or quinazolinyl (also known as“1,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or“isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, benzothienyl (also known as“benzothiophenyl,” “thionaphthenyl,” or “benzothiofuranyl”),isobenzothienyl (also known as “isobenzothiophenyl,”“isothionaphthenyl,” or “isobenzothiofuranyl”), benzothiazolyl,benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, andacridinyl.

The term “heteroaryl” also includes substituents such as pyridyl andquinolinyl that are fused to a C₄-C₁₀ carbocyclic ring, such as a C₅ ora C₆ carbocyclic ring, or to a 4- to 10-membered heterocyclic ring,wherein a group having such a fused heteroaryl group as a substituent isbound to an aromatic carbon of the heteroaryl group or to a heteroatomof the heteroaryl group. When such a fused heteroaryl group issubstituted with one or more substituents, the one or more substituents,unless otherwise specified, are each bound to an aromatic carbon of theheteroaryl group or to a heteroatom of the heteroaryl group. The fusedC₄-C₁₀ carbocyclic or 4- to 10-membered heterocyclic ring may beoptionally substituted with halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or ═O.

Additional examples of heteroaryls and heterocycloalkyls include but arenot limited to: 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzo[1,3]dioxine, benzo[1,4]dioxine, benzopyrrolidinyl,benzopiperidinyl, benzoxolanyl, benzothiolanyl,4,5,6,7-tetrahydropyrazol[1,5-a]pyridine, benzothianyl, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl,quinolizinyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. The foregoing groups, as derived fromthe groups listed above, may be C-attached or N-attached where such ispossible. For instance, a group derived from pyrrole may be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). Further, a group derived fromimidazole may be imidazol-1-yl (N-attached) or imidazol-2-yl(C-attached).

A substituent is “substitutable” if it comprises at least one carbon ornitrogen atom that is bonded to one or more hydrogen atoms. Thus, forexample, hydrogen, halogen, and cyano do not fall within thisdefinition.

If a substituent is described as being “substituted,” a non-hydrogensubstituent is in the place of a hydrogen substituent on a carbon ornitrogen of the substituent. Thus, for example, a substituted alkylsubstituent is an alkyl substituent wherein at least one non-hydrogensubstituent is in the place of a hydrogen substituent on the alkylsubstituent. To illustrate, monofluoroalkyl is alkyl substituted with afluoro substituent, and difluoroalkyl is alkyl substituted with twofluoro substituents. It should be recognized that if there is more thanone substitution on a substituent, each non-hydrogen substituent may beidentical or different (unless otherwise stated).

If a substituent is described as being “optionally substituted,” thesubstituent may be either (1) not substituted, or (2) substituted. If acarbon of a substituent is described as being optionally substitutedwith one or more of a list of substituents, one or more of the hydrogenson the carbon (to the extent there are any) may separately and/ortogether be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogens on the nitrogen (to the extent there are any)may each be replaced with an independently selected optionalsubstituent. One exemplary substituent may be depicted as —NR′R″,wherein R′ and R″ together with the nitrogen atom to which they areattached may form a heterocyclic ring comprising 1 or 2 heteroatomsindependently selected from oxygen, nitrogen, or sulfur, wherein saidheterocycloalkyl moiety may be optionally substituted. The heterocyclicring formed from R′ and R″ together with the nitrogen atom to which theyare attached may be partially or fully saturated, or aromatic. In oneembodiment, the heterocyclic ring consists of 4 to 10 atoms. In anotherembodiment, the heterocyclic ring is selected from the group consistingof piperidinyl, morpholinyl, azetidinyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl and tetrazolyl.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If a group of substituents are collectively described as beingoptionally substituted by one or more of a list of substituents, thegroup may include: (1) unsubstitutable substituents, (2) substitutablesubstituents that are not substituted by the optional substituents,and/or (3) substitutable substituents that are substituted by one ormore of the optional substituents.

If a substituent is described as being optionally substituted with up toa particular number of non-hydrogen substituents, that substituent maybe either (1) not substituted; or (2) substituted by up to thatparticular number of non-hydrogen substituents or by up to the maximumnumber of substitutable positions on the substituent, whichever is less.Thus, for example, if a substituent is described as a heteroaryloptionally substituted with up to 3 non-hydrogen substituents, then anyheteroaryl with less than 3 substitutable positions would be optionallysubstituted by up to only as many non-hydrogen substituents as theheteroaryl has substitutable positions. To illustrate, tetrazolyl (whichhas only one substitutable position) would be optionally substitutedwith up to one non-hydrogen substituent. To illustrate further, if anamino nitrogen is described as being optionally substituted with up to 2non-hydrogen substituents, then the nitrogen will be optionallysubstituted with up to 2 non-hydrogen substituents if the amino nitrogenis a primary nitrogen, whereas the amino nitrogen will be optionallysubstituted with up to only 1 non-hydrogen substituent if the aminonitrogen is a secondary nitrogen.

A prefix attached to a multi-moiety substituent only applies to thefirst moiety. To illustrate, the term “alkylcycloalkyl” contains twomoieties: alkyl and cycloalkyl. Thus, a C₁₋₆— prefix onC₁₋₆alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkylcontains from 1 to 6 carbon atoms; the C₁₋₆— prefix does not describethe cycloalkyl moiety. To illustrate further, the prefix “halo” onhaloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkylsubstituent is substituted with one or more halogen substituents. If thehalogen substitution only occurs on the alkyl moiety, the substituentwould be described as “alkoxyhaloalkyl.” If the halogen substitutionoccurs on both the alkyl moiety and the alkoxy moiety, the substituentwould be described as “haloalkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other(s). Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

It is understood that descriptions of any one substituent, such as R¹,may be combined with descriptions of any other substituents, such as R²,such that each and every combination of the first substituent and thesecond substituent is provided herein the same as if each combinationwere specifically and individually listed. For example, in onevariation, R¹ is taken together with R² to provide an embodiment whereinR¹ is methyl and R² is halogen.

As used herein the term “Formula I” may be hereinafter referred to as a“compound(s) of the invention.” Such terms are also defined to includeall forms of the compound of Formula I, including hydrates, solvates,isomers, crystalline and non-crystalline forms, isomorphs, polymorphs,and metabolites thereof. For example, the compounds of Formula I, orpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

The compounds of Formula I may exist as clathrates or other complexes.Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of Formula Icontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August1975).

The compounds of Formula I may have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of Formula I may be depicted hereinusing a solid line (—), a solid wedge (

) or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g. specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of Formula I maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof Formula I can exist as enantiomers and diastereomers or as racematesand mixtures thereof. The use of a solid line to depict bonds to one ormore asymmetric carbon atoms in a compound of Formula I and the use of asolid or dotted wedge to depict bonds to other asymmetric carbon atomsin the same compound is meant to indicate that a mixture ofdiastereomers is present.

Stereoisomers of Formula I include cis and trans isomers, opticalisomers such as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, conformational isomers, and tautomers of thecompounds of Formula I, including compounds exhibiting more than onetype of isomerism; and mixtures thereof (such as racemates anddiastereomeric pairs). Also included are acid addition or base additionsalts wherein the counterion is optically active, for example, D-lactateor L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula I above, but for thefact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that may be incorporatedinto compounds of Formula I include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but notlimited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.Certain isotopically-labeled compounds of Formula I, for example thoseinto which radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Tritiated,i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferredfor their ease of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically-labeledcompounds of Formula I may generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting an isotopically-labeled reagent fora non-isotopically-labeled reagent.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of formula I with anacid whose anion, or a base whose cation, is generally consideredsuitable for human consumption. Pharmaceutically acceptable salts areparticularly useful as products of the methods of the present inventionbecause of their greater aqueous solubility relative to the parentcompound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude but are not limited to aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic, and sulfonic classes of organicacids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, butyrate, camphorate,camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalenesulfonate, oxalate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, i.e., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (i.e., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (i.e.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulphate and hemicalcium salts.

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts. Theterm “therapeutically effective amount” as used herein refers to thatamount of the compound being administered which will relieve to someextent one or more of the symptoms of the disorder being treated.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beadministered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the invention canalso be administered intranasally or by inhalation. In anotherembodiment, the compounds of the invention may be administered rectallyor vaginally. In another embodiment, the compounds of the invention mayalso be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient. A medicament typically contains from about 0.01 mg to about 500mg of the active ingredient, or in another embodiment, from about 1 mgto about 100 mg of active ingredient. Intravenously, doses may rangefrom about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compounds ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be Formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of Formula I areordinarily combined with one or more adjuvants. Such capsules or tabletsmay contain a controlled-release Formulation. In the case of capsules,tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (i.e.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be Formulated according to the known art using suitabledispersing, wetting, and/or suspending agents.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalFormulation may include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical Formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, Finnin and Morgan, J.Pharm. Sci., 88 (10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical Formulation suitable forocular or aural administration may be in the form of drops of amicronised suspension or solution in isotonic, pH-adjusted, sterilesaline. Other Formulations suitable for ocular and aural administrationinclude ointments, biodegradable (i.e., absorbable gel sponges,collagen) and non-biodegradable (i.e., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose,or a heteropolysaccharide polymer, for example, gelan gum, may beincorporated together with a preservative, such as benzalkoniumchloride. Such Formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone; as amixture, for example, in a dry blend with lactose; or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective Formulation and administration procedures.The above considerations in regard to effective Formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. An exemplary therapeutic agent may be, for example, ametabotropic glutamate receptor agonist.

The administration of two or more compounds “in combination” means thatthe two compounds are administered closely enough in time that thepresence of one alters the biological effects of the other. The two ormore compounds may be administered simultaneously, concurrently orsequentially. Additionally, simultaneous administration may be carriedout by mixing the compounds prior to administration or by administeringthe compounds at the same point in time but at different anatomic sitesor using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

In another embodiment, the invention relates to the novel intermediatesuseful for preparing the compounds of the invention. For example, thecompound of Formula II is useful for preparing the compounds of theinvention.

The compounds of Formula II may exhibit the phenomenon of tautomerism.For example, the compounds of Formula II may exist in several tautomericforms, including the pyridone form, IIa, and the hydroxypyridine form,IIb. All such tautomeric forms are included within the scope ofcompounds of Formula II. Tautomers exist as mixtures of a tautomeric setin solution. In solid form, usually one tautomer predominates. Eventhough one tautomer may be described, the present invention includes alltautomers of the compounds of Formula II and salts thereof. Examples oftautomers are described by the compounds of Formula IIa and IIb.

Examples of the salt forms of the tautomers are described by thecompounds of Formula IIai, IIaii, IIbi,

When intermediates used to synthesize compounds of the present inventionincorporate a basic center their suitable acid addition salts may beemployed in synthetic pathways. Such suitable addition salts include butare not limited to those derived from inorganic acids, such ashydrochloric, hydrobromic, hydrofluoric, hydroiodic, boric, fluoroboric,phosphoric, nitric, carbonic, and sulfuric acids, and organic acids suchas acetic, benzenesulfonic, benzoic, ethanesulfonic, fumaric, lactic,maleic, methanesulfonic, trifluoromethanesulfonic, succinic,toluenesulfonic, and trifluoroacetic acids. Suitable organic acidsgenerally include but are not limited to aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, lactate,maleate, fumarate, benzoate, p-hydroxybenzoate, phenylacetate,mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, adipate, butyrate, camphorate, cyclopentanepropionate,dodecylsulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate,oxalate, 3-phenylpropionate, pivalate, and undecanoate.

Furthermore, where intermediates used to prepare compounds of theinvention carry an acidic moiety, suitable salts thereof may be employedfor synthesis. Such salts include alkali metal salts, i.e., lithium,sodium or potassium salts; alkaline earth metal salts, e.g., calcium ormagnesium salts; and salts formed with suitable organic ligands such asamines or quaternary ammonium cations. Organic salts of such acidicintermediates may be made from primary, secondary or tertiary aminessuch as methylamine, diethylamine, ethylenediamine or trimethylamine.Quaternary amines may be prepared by reaction of tertiary amines withagents such as lower alkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl,and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e.,dimethyl, diethyl, dibutyl, and diamyl sulfates), arylalkyl halides(i.e., benzyl and phenethyl bromides), and others.

Examples of such compound Formula II intermediate salt forms aredepicted below:

The compounds of Formulas I and II may be prepared by the methodsdescribed below, together with synthetic methods known in the art oforganic chemistry, or modifications and derivatizations that arefamiliar to those of ordinary skill in the art. The starting materialsused herein are commercially available or may be prepared by routinemethods known in the art (such as those methods disclosed in standardreference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS,Vol. I-XII (published by Wiley-Interscience)). Preferred methodsinclude, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formula I, or their pharmaceutically acceptable salts, canbe prepared according to the reaction Schemes discussed herein below.Unless otherwise indicated, the substituents in the Schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the schemes, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the schemes, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. The schemes are representative ofmethods useful in synthesizing the compounds of the present invention.They are not to constrain the scope of the invention in any way.

Scheme 1 illustrates a method for preparing compounds of Formula I. Acompound of Formula 1.1 is heated in the presence of an aqueous acidsuch as hydrochloric acid to furnish the corresponding pyridinone acidof Formula 1.2. The intermediate of Formula 1.2 is subjected to an amidecoupling and in situ cyclization reaction with amino alcohol of Formula1.3 using a coupling reagent such as HATU[O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate]. The reaction is carried out in the presence of asuitable base such as diisopropylethyl amine and in a solvent such asdichloromethane, or dimethylformamide.

Scheme 2 illustrates a method for the preparation of compounds ofFormula I. This method commences with the reductive amination ofchloroaledehyde (2.1) and an amine of Formula 2.2 using one of manyreductive amination protocols known to those skilled in the art. Forexample, this reaction may be carried out by using a reducing agent suchas sodium triacetoxyborohydride in a suitable solvent such as methanol.Following purification, the resultant chloroethylamine 2.3 may beisolated and stored as its HCl salt. The final compound of Formula I maythen be prepared by treating a mixture of chloroalkylamine 2.3, acid1.2, and a base such as diisopropylethylamine with a suitable amidecoupling reagent such as BOP-Cl [(bis(2-oxo-3-oxazolidinyl)phosphonicchloride], T3P [propylphosphonic anhydride] or HATU (preferably HATU) ina solvent such as dichloromethane.

Scheme 3 illustrates a method for the preparation of compounds ofFormula 3.4. An acid of Formula 1.2 is treated withbis(2-chloroethyl)amine (3.1), a base such as K₂CO₃, and an amidecoupling reagent such as HATU in a suitable solvent such as DMF. Theresulting intermediate of Formula 3.2 is then coupled to a compound ofFormula 3.3 by heating in the presence of a suitable base such as K₂CO₃in a solvent such as DMF or DMSO to afford the final compound of Formula3.4.

Scheme 4 illustrates a method for the preparation of compounds ofFormula 1.1 where R¹—X=4-methylimidazole. A 3-aminopyridine compound ofFormula 4.1 is brominated using N-bromosuccinamide in a solvent such asa mixture of DMSO and water. The resulting intermediate of Formula 4.2is then heated with sodium methoxide in a suitable solvent such as1,4-dioxane to afford a compound of Formula 4.3. The intermediate ofFormula 4.3 is then treated with a mixture of acetic anhydride andformic acid to afford a formamide of Formula 4.4, which is alkylatedwith chloroacetone in the presence of potassium iodide and a base suchas Cs₂CO₃ in a suitable solvent such as DMF. The resulting intermediateof Formula 4.5 is then heated in the presence of NH₄OAc in acetic acidto furnish the imidazole derivative 4.6. Finally, the compound ofFormula 1.1 can be prepared by subjecting the intermediate of Formula4.6 to a carbonylation reaction. This transformation may be carried outby heating a solution of 4.6 and a base such as triethylamine in asuitable alcohol solvent such as methanol under an atmosphere of CO inthe presence of a suitable palladium catalyst such as Pd(dppf)₂Cl₂.DCM[1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex].

Scheme 5 depicts a method for the preparation of compounds of Formula1.1. A pyridyl derivative of Formula 5.1 is oxidized with an oxidizingagent such as mCPBA [meta-chloroperbenzoic acid] in a suitable solventsuch as dichloroethane to afford the corresponding N-oxide of Formula5.2. The intermediate of Formula 5.2 is then heated in the presence ofTMSCN [trimethylsilyl cyanide] and a base such as triethylamine in asolvent such as acetonitrile to afford the intermediate of Formula 5.3.The ethyl ester of Formula 5.5 may then be prepared from 5.3 in twosteps by subjecting 5.3 to sodium methoxide in a solvent such as THFfollowed by treatment with EtOH and an acid such as HCl. The ester ofFormula 5.5 is a versatile intermediate that allows introduction of avariety of heterocycles X. For example, 5.5 may be subjected to a Suzukicoupling with a heteroaryl boronic acid using methods well known tothose skilled in the art [see Tetrahedron 2002, 58, 9633-9695].Alternatively, the compound of Formula 5.5 may be coupled to aheterocycle R¹X using a direct arylation approach [see J. Org. Chem.2011, DOI: 10.1021/jo102081a, and references therein]. For example, 5.5may be coupled to 2-methyl-1,3-oxazole [Formula 5.7 where R¹=Me] byheating in the presence of a suitable palladium-catalyst such asallylpalladium chloride dimer and a base such as K₂CO₃ in a solvent suchas 1,4-dioxane to afford the intermediate of Formula 1.1 where X=oxazoleand R¹=Me.

Alternatively, the compound of Formula 5.5 may be converted to thecorresponding boronate 5.6, using a palladium catalyzed cross couplingwith a diboron reagent such as5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane in the presence ofpotassium acetate and a palladium catalyst such as Pd(dppf)₂Cl₂.DCM in asolvent such as 1,4-dioxane. The resulting boronate intermediate ofFormula 5.6 can in turn be subjected to a Suzuki coupling with aheteroaryl halide to afford the final compound of Formula 1.1. Anothermethod for the introduction of a heterocycle X involves the use of aChan-Lam coupling [see Tetrahedron Lett. 2003, 44, 3863-3865, andSynthesis, 2008, 5, 795-799]. For example, 5.6 may be coupled tosubstituted imidazole 5.8 by heating with copper oxide in a solvent suchas methanol in the presence of air to afford the intermediate of Formula1.1 where X=imidazole.

Scheme 6 illustrates a method for the synthesis of compounds of FormulaI. The method commences by heating the compound of Formula 6.1 in anacid such as hydrochloric acid to afford pyridinone acid intermediate6.2. The acid of Formula 6.2 may be subjected to a coupling/cyclizationreaction with an aminoalcohol of Formula 1.3 to afford an intermediateof Formula 6.3 using chemistry described in Scheme 1. The finalcompound, Formula I, may then be formed directly from 6.3 or viaboronate 6.4 using the strategies discussed in detail for Scheme 5.Alternatively, compounds of Formula I where heterocycle X is linked tothe pyridinone ring via a C—N bond may be formed by nucleophilicaromatic substitution. For example, triazole 6.5 may be coupled to 6.3by heating in the presence of a base such as K₂CO₃ and a solvent such asDMSO to afford the final compound of Formula I where X=triazole.

The aminoalcohol coupling partner of Formula 1.3 may be prepared via awide variety of synthetic methods, which can readily be envisioned anddeveloped by one skilled in the art. These include, but are not limitedto, those methods illustrated in Scheme 7. For example, the aminoalcoholof Formula 1.3 may be prepared by carrying out a reductive amination ofa ketone of Formula 7.1 with an amine of Formula 2.2 using one of manyprocedures well-known to those skilled in the art. Another methodinvolves reductive amination of an aldehyde of Formula 7.2 with an amineof Formula 2.2 followed by removal of the TBS protecting group by usinga suitable procedure including treatment with methanolic HCl ortetrabutylammonium fluoride. Another example of a representative methodfor the synthesis of an aminoalcohol of Formula 1.3 involves alkylationof amine 7.3 with a halide or mesylate of Formula 7.4. Yet anothermethod involves alkylation of an amine of Formula 2.2 with2-bromoalcohol 7.5.

Experimental Procedures and Working Examples

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

It will be understood that the intermediate compounds of the inventiondepicted above are not limited to the particular enantiomer shown, butalso include all stereoisomers and mixtures thereof. It will also beunderstood that compounds of Formula I can include intermediates ofcompounds of Formula I.

Experimental Procedures

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification, includinganhydrous solvents where appropriate (generally Sure-Seal™ products fromthe Aldrich Chemical Company, Milwaukee, Wis.). Products were generallydried under vacuum before being carried on to further reactions orsubmitted for biological testing. Mass spectrometry data is reportedfrom either liquid chromatography-mass spectrometry (LCMS), atmosphericpressure chemical ionization (APCI) or gas chromatography-massspectrometry (GCMS) instrumentation. Chemical shifts for nuclearmagnetic resonance (NMR) data are expressed in parts per million (ppm,δ) referenced to residual peaks from the deuterated solvents employed.

For syntheses referencing procedures in other Examples or Methods,reaction conditions (length of reaction and temperature) may vary. Ingeneral, reactions were followed by thin layer chromatography or massspectrometry, and subjected to work-up when appropriate. Purificationsmay vary between experiments: in general, solvents and the solventratios used for eluants/gradients were chosen to provide appropriateR_(f)s or retention times.

PREPARATIONS Preparation 15-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrobromide salt (P1)

Step 1. Synthesis of methyl6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2). To asolution of the known6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (C1, T. Kimuraet al., U.S. Pat. Appl. Publ. (2009), US 20090062529 A1) (44.2 g, 165mmol) in methanol (165 mL) was added triethylamine (46 mL, 330 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (6.7 g, 8.24 mmol). The mixture was degassedseveral times with nitrogen. The reaction was heated to 70° C. under COatmosphere (3 bar) in a Parr apparatus. After 30 minutes, the pressuredropped to 0.5 bar; additional CO was added until the pressure stayedconstant for a period of 30 minutes. The mixture was allowed to cool toroom temperature and filtered through a pad of Celite. The Celite padwas washed twice with methanol and the combined filtrates wereconcentrated under reduced pressure. The residue (88 g) was dissolved inethyl acetate (1 L) and water (700 mL), and the layers were separated.The organic layer was washed with water (200 mL), and the aqueous layerwas extracted with ethyl acetate (500 mL). The combined organic layerswere dried over magnesium sulfate, filtered and concentrated to providethe title compound. Yield: 42.6 g, 175 mmol, quantitative.

Step 2. Synthesis of5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrobromide salt (P1)A solution of methyl6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2) (3.82g, 15.9 mmol) in acetic acid (30 mL) and aqueous hydrobromic acid (48%,30 mL) was heated at reflux for 4 hours. The reaction was allowed tocool to room temperature, then chilled in an ice bath; the resultingprecipitate was collected via filtration and washed with ice water (30mL). Recrystallization from ethanol (20 mL) provided the title compoundas a light yellow solid. Yield: 3.79 g, 12.6 mmol, 79%. LCMS m/z 220.1(M+1). ¹H-NMR (400 MHz, DMSO-d₆) δ 2.34 (br s, 3H), 7.09 (d, J=7.4 Hz,1H), 7.88-7.91 (m, 1H), 8.07 (d, J=7.6 Hz, 1H), 9.58-9.60 (m, 1H), 12.6(v br s, 1H).

Preparation 22-(2-Chloroethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P2)

Step 1. Synthesis of5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrochloride salt (C3). A solution of6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2) (34.3g, 139 mmol) in aqueous hydrochloric acid (37%, 230 mL) and 1,4-dioxane(230 mL) was heated at reflux for 18 hours. After cooling to roomtemperature, the reaction was filtered and the solids were washed with1,4-dioxane (2×100 mL). The solids were mixed with methanol (500 mL) andthe volatiles were removed in vacuo. The residue was stirred withmethanol (100 mL) for 15 minutes, and 1,4-dioxane (250 mL) was added.The resulting mixture was stirred for 15 minutes; the solids werecollected by filtration and washed with 1,4-dioxane to provide the titlecompound as a beige solid. Yield: 35.4 g, 138 mmol, 99%. ¹H NMR (300MHz, DMSO-d₆) δ 2.33 (d, J=0.9 Hz, 3H), 7.09 (d, J=7.5 Hz, 1H),7.84-7.87 (m, 1H), 8.04 (d, J=7.5 Hz, 1H), 9.50 (d, J=1.6 Hz, 1H).

Step 2. Synthesis of242-chloroethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P2). Potassium carbonate (195.4 g, 1414 mmol) was added to a mixture of5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrochloride salt (C3) (34.5 g, 135 mmol) and2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (37.8 g, 212 mmol) inN,N-dimethylformamide (670 mL), and the reaction was stirred for 10minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 83.5 g, 219 mmol) was added and stirring wascontinued for an additional 3 hours and 40 minutes. The reaction mixturewas then poured into water (4 L) and stirred for 30 minutes. Afterextraction with dichloromethane (3×1 L), the combined organic layerswere washed with saturated aqueous sodium chloride solution (3×3 L),dried over magnesium sulfate, filtered and concentrated in vacuo.Finally, most of the DMF was removed by using a methanol/liquid nitrogencooler. The residue was stirred in ethyl acetate (approximately 50 mL)for 30 minutes. The solids were collected by filtration and washed withethyl acetate and pentane, providing the title compound as a yellowsolid. Yield: 23.0 g, 75.0 mmol, 56%. LCMS m/z 307.1 (M+1). ¹H-NMR (300MHz, CDCl₃) δ 2.29 (br s, 3H), 3.80-3.93 (m, 6H), 4.38-4.44 (m, 2H),7.13-7.16 (m, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 8.24(d, J=1.0 Hz, 1H).

Preparation 32-[(2-{2-[2-(Trifluoromethyl)-1,3-thiazol-4-yl]phenoxy}ethyl)amino]ethanol(P3)

Step 1. Synthesis of 2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenol (C4)2,2,2-Trifluoroethanethioamide (which may be prepared by the method ofJ. H. Hillhouse et al., Phosphorus, Sulfur Relat. Elem. 1986, 26,169-84) (157 mg, 1.22 mmol) in ethanol (1.3 mL) was added drop-wise to asolution of 2-bromo-1-(2-hydroxyphenyl)ethanone (119 mg, 0.55 mmol) inethanol (1.3 mL) and the reaction was refluxed overnight. The reactionwas concentrated in vacuo and purified via silica gel chromatography(Gradient: 5% to 20% ethyl acetate in heptane) to afford the titlecompound. Yield: 67 mg, 0.27 mmol, 49%. LCMS m/z 246.0 (M+1). ¹H NMR(400 MHz, CDCl₃) δ 6.95 (ddd, J=8, 7, 1 Hz, 1H), 7.07 (dd, J=8.2, 1.2Hz, 1H), 7.33 (ddd, J=8, 7, 2 Hz, 1H), 7.64 (dd, J=7.8, 1.6 Hz, 1H),7.81 (s, 1H), 10.47 (s, 1H).

Step 2. Synthesis of4-[2-(2-bromoethoxy)phenyl]-2-(trifluoromethyl)-1,3-thiazole (C5) Cesiumcarbonate (266 mg, 0.816 mmol) was added to a solution of2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenol (C4) (100 mg, 0.408 mmol)and 1,2-dibromoethane (0.35 mL, 4.1 mmol) in acetonitrile (33 mL), andthe mixture was heated at 70° C. for 18 hours. After cooling to roomtemperature, the reaction was partitioned between dichloromethane andwater; the organic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Purification via silica gel chromatography(Gradient: 10% to 30% ethyl acetate in heptane) afforded the titlecompound. Yield: 115 mg, 0.327 mmol, 80%. ¹H NMR (400 MHz, CDCl₃) δ 3.78(br dd, J=5.5, 5.5 Hz, 2H), 4.48 (dd, J=5.7, 5.5 Hz, 2H), 6.97 (br d,J=8.4 Hz, 1H), 7.13 (ddd, J=7.7, 7.4, 1.1 Hz, 1H), 7.35 (ddd, J=8.3,7.3, 1.8 Hz, 1H), 8.31 (dd, J=7.8, 1.8 Hz, 1H), 8.37 (s, 1H).

Step 3. Synthesis of2-[(2-{2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenoxy}ethyl)amino]ethanol(P3). A mixture of4-[2-(2-bromoethoxy)phenyl]-2-(trifluoromethyl)-1,3-thiazole (C5) (115mg, 0.327 mmol) and 2-aminoethanol (0.197 mL, 3.26 mmol) was heated to80° C. for 3 hours. After cooling to room temperature, the reaction wasdiluted with dichloromethane and washed with 0.5 N aqueous sodiumhydroxide solution, then with water. The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo, yielding thetitle compound as a white solid. Yield: 113 mg, quantitative. ¹H NMR(400 MHz, CDCl₃) δ 2.88 (dd, J=5.2, 5.1 Hz, 2H), 3.15 (dd, J=5, 5 Hz,2H), 3.68 (br dd, J=5, 5 Hz, 2H), 4.25 (dd, J=5, 5 Hz, 2H), 7.03 (br d,J=8.3 Hz, 1H), 7.08-7.12 (m, 1H), 7.33-7.38 (m, 1H), 8.18 (s, 1H), 8.21(br d, J=7.9 Hz, 1H).

Preparation 42-({(2S)-1-[4-Fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}amino)ethanol,hydrochloride salt (P4)

Step 1. Synthesis oftert-butyl{(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}carbamate(C6). To a mixture of tert-butyl[(2S)-1-hydroxypropan-2-yl]carbamate(1.07 g, 6.11 mmol), 4-fluoro-2-(trifluoromethyl)phenol (1.10 g, 5.55mmol) and triphenylphosphine-resin (2.80 g, 8.40 mmol) intetrahydrofuran (50 mL) was added drop-wise diisopropyl azodicarboxylate(DIAD, 1.37 g, 6.66 mmol). The reaction was allowed to stir at roomtemperature for 3 days, then filtered and rinsed with ethyl acetate. Thecombined filtrate was washed with 0.5 N aqueous sodium hydroxide andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification via silica gelchromatography (50% ethyl acetate in heptane) afforded the titlecompound as a clear yellow oil. Sample contained some residualdiisopropyl azodicarboxylate and carried forward without furtherpurification. Yield: 2.52 g, 134%. LCMS m/z 282.0{[M-(2-methyl-prop-1-ene)]+1}. ¹H NMR (400 MHz, CDCl₃) δ 1.31 (d, J=6.8Hz, 3H), 1.45 (s, 9H), 3.98-4.03 (m, 2H), 4.04-4.13 (m, 1H), 6.95 (dd,J=9.2, 4.2 Hz, 1H), 7.16-7.22 (m, 1H), 7.30 (dd, J=8.3, 3.0 Hz, 1H).

Step 2. Synthesis of(2S)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7). To asolution oftert-butyl{(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}carbamate(C6) (1.87 g, 5.54 mmol) in methanol (10 mL) was added a solution ofhydrogen chloride (4 N in 1,4-dioxane, 5 mL). After 4 hours, thereaction mixture was concentrated in vacuo. The resulting residue wastaken up in dichloromethane and washed with saturated aqueous sodiumbicarbonate solution and water. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0 to 20% methanol in ethyl acetate)afforded the title compound as a yellow liquid. Yield: 785 mg, 3.31mmol, 60%. LCMS m/z 238.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (d,J=6.5 Hz, 3H), 3.35-3.44 (m, 1H), 3.74 (dd, J=8.4, 7.4 Hz, 1H), 3.94(dd, J=8.5, 4.0 Hz, 1H), 6.93 (dd, J=9.1, 4.2 Hz, 1H), 7.18 (br ddd,J=9, 8, 3 Hz, 1H), 7.30 (dd, J=8.4, 3.1 Hz, 1H).

Step 3. Synthesis of(2S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine(C8). To a solution of(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7) (785 mg,3.31 mmol) in dichloromethane (15 mL) was added{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (577 mg, 3.31 mmol). After2 hours, sodium triacetoxyborohydride was added portion-wise. Thereaction mixture was allowed to stir at room temperature overnight, thentaken up in dichloromethane and washed with saturated aqueous sodiumbicarbonate solution and water. The organic layer was concentrated invacuo, then purified via silica gel chromatography (Gradient: 0 to 7%methanol in ethyl acetate) to afford the title compound as a clearliquid. Yield: 466 mg, 1.18 mmol, 36%. LCMS m/z 396.2 (M+1). ¹H NMR (400MHz, CDCl₃) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.19 (d, J=6.4 Hz, 3H),2.73-2.86 (m, 2H), 3.11-3.19 (m, 1H), 3.74 (dd, J=5.6, 5.4 Hz, 2H), 3.92(d, J=5.5 Hz, 2H), 6.94 (dd, J=9.0, 4.0 Hz, 1H), 7.15-7.21 (m, 1H), 7.29(dd, J=8.4, 3.1 Hz, 1H).

Step 4. Synthesis of2-({(2S)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}amino)ethanol,hydrochloride salt (P4). To a solution of(2S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine(C8) (460 mg, 1.16 mmol) in methanol (5 mL) was added a solution ofhydrogen chloride (4N in dioxane, 2 mL). After 4 hours, the reactionmixture was concentrated in vacuo to afford the title compound as aclear gum. Yield: 398 mg, 100%. LCMS m/z 282.0 (M+1). ¹H NMR (400 MHz,CD₃OD) δ 1.51 (d, J=6.8 Hz, 3H), 3.28-3.32 (m, 2H, assumed; largelyobscured by solvent peak), 3.80-3.87 (m, 1H), 3.84 (dd, J=5.3, 5.2 Hz,2H), 4.29 (dd, half of ABX pattern, J=10.6, 5.8 Hz, 1H), 4.38 (dd, halfof ABX pattern, J=10.6, 4.0 Hz, 1H), 7.30 (dd, J=9.0, 4.2 Hz, 1H),7.38-7.45 (m, 2H).

Preparation 5 2-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (P5)

Step 1. Synthesis of 4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione(C9). To a suspension of sodium hydride (60% in mineral oil, 202 mg, 8.0mmol) in 1,2-dimethoxyethane (4 mL) was added drop-wise ethyltrifluoroacetate (954 μL, 8.0 mmol) followed by1-(2-methoxyphenyl)ethanone (552 μL, 4.0 mmol) and the reaction washeated to 160° C. in a microwave for 15 minutes. Aqueous hydrochloricacid (1 N, 20 mL) was added and the mixture was extracted withtert-butyl methyl ether (3×10 mL). The combined organic layers weredried over sodium sulfate and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 10% tert-butyl methyl etherin heptanes) afforded the title compound as a red solid. Yield: 933 mg,3.79 mmol, 95%. GCMS m/z 246 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 3.96 (s,3H), 6.99 (s, 1H), 7.02 (br d, J=8.5 Hz, 1H), 7.08 (ddd, J=8, 7, 1.0 Hz,1H), 7.55 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 7.99 (dd, J=7.9, 1.9 Hz, 1H).

Step 2. Synthesis of 5-(2-methoxyphenyl)-3-(trifluoromethyl)-1,2-oxazole(C10) A mixture of 4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione(C9) (933 mg, 3.79 mmol) and hydroxylamine hydrochloride (798 mg, 11.4mmol) in ethanol (10 mL) was refluxed under nitrogen for 3 hours, thencooled to room temperature. The reaction was concentrated in vacuo,treated with water (30 mL) and extracted with dichloromethane (3×10 mL).The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Purification via silica gel chromatography(Gradient: 0% to 20% ethyl acetate in heptanes) afforded the titlecompound as a yellow oil. Yield: 502 mg, 2.06 mmol, 54%. GCMS m/z 243(M⁺). ¹H NMR (400 MHz, CDCl₃) δ 4.00 (s, 3H), 7.01 (s, 1H), 7.05 (dd,J=8.4, 0.9 Hz, 1H), 7.11 (ddd, J=7.8, 7.4, 1.1 Hz, 1H), 7.48 (ddd,J=8.4, 7.4, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H).

Step 3. Synthesis of 2-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol (P5).To a mixture of 5-(2-methoxyphenyl)-3-(trifluoromethyl)-1,2-oxazole(C10) (502 mg, 2.06 mmol) and tetra-n-butylammonium iodide (915 mg, 2.48mmol) in dichloromethane (20 mL) cooled to −78° C. was added borontrichloride (1 M in dichloromethane, 4.95 mL, 4.95 mmol). The reactionwas allowed to stir at room temperature for 24 hours, and then cooled to−78° C., whereupon methanol (3 mL) was slowly added followed by water(30 mL). The mixture was extracted with dichloromethane (2×10 mL), andthe combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Purification via silica gel chromatography(Gradient: 0% to 20% tert-butyl methyl ether in heptanes) afforded thetitle compound as a white solid. Yield: 283 mg, 1.23 mmol, 60%. ¹H NMR(400 MHz, CDCl₃) δ 5.94 (s, 1H), 6.96 (br d, J=8.2 Hz, 1H), 7.02 (s,1H), 7.09 (br dd, J=8, 8 Hz, 1H), 7.39 (ddd, J=8, 8, 1.6 Hz, 1H), 7.89(dd, J=7.9, 1.7 Hz, 1H).

Preparation 6 4-Fluoro-2-(trifluoromethyl)-1,3-benzothiazol-7-ol (P6)

Step 1. Synthesis of 1-(2-fluoro-5-methoxyphenyl)thiourea (C11) To asolution of benzoyl isothiocyanate (20.20 g, 123.9 mmol) in acetone (350mL) at 60° C. was added a solution of 2-fluoro-5-methoxyaniline (15.90g, 112.6 mmol) in acetone (60 mL). The reaction mixture was refluxed for2 hours and cooled to room temperature. The solution was concentrated toa volume of approximately 100 mL and then poured into ice water (900mL). The resulting precipitate was collected, washed with water andhexanes, and dried at 40° C. under vacuum. It was then added into asolution of sodium hydroxide (15.00 g, 375.0 mmol) in water (300 mL) at80° C. Heating was continued for 2 hours. After the reaction had cooledto room temperature, the pH was adjusted to 10 with concentratedhydrochloric acid. The precipitate was collected by filtration andwashed with saturated aqueous sodium bicarbonate solution (2×250 mL),water (2×250 mL) and hexanes (2×250 mL) to afford the title compound asa white solid. Yield: 17.40 g, 86.9 mmol, 77%. ¹H NMR (300 MHz, CDCl₃) δ3.86 (s, 3H), 6.13 (br s, 1H), 6.82 (m, 1H), 6.90 (m, 1H), 7.13 (m, 1H),7.63 (br s, 1H).

Step 2. Synthesis of 4-fluoro-7-methoxy-1,3-benzothiazol-2-amine (C12).To a suspension of 1-(2-fluoro-5-methoxyphenyl)thiourea (C11) (17.30 g,86.40 mmol) in chloroform (160 mL) at 0° C. was added bromine (4.44 mL,86.4 mmol) drop-wise. The reaction mixture was stirred at roomtemperature for 30 minutes and was then heated to reflux for 18 hours.It was poured into ice water (1.0 L) containing an excess of sodiumbicarbonate. The resulting precipitate was collected by filtration andwashed with water and hexanes to afford the title compound as a whitesolid. Yield: 15.40 g, 77.69 mmol, 90%. ¹H NMR (300 MHz, DMSO-d₆): 3.84(s, 3H), 6.60 (m, 1H), 7.03 (m, 1H), 7.73 (s, 2H),

Step 3. Synthesis of 4-fluoro-7-methoxy-1,3-benzothiazole (C13) To asolution of 4-fluoro-7-methoxy-1,3-benzothiazol-2-amine (C12) (15.40 g,77.69 mmol) in 1,4-dioxane (700 mL) was added isoamyl nitrite (15.0 mL,111.6 mmol). The reaction mixture was stirred at 85° C. for 18 hours andthen cooled to room temperature. The solvent was removed in vacuo, andpurification was carried out with silica gel chromatography (Eluant: 1:1dichloromethane/hexanes) to afford the title compound as a yellow solid.Yield: 12.0 g, 65.5 mmol, 84%. ¹H NMR (300 MHz, CDCl₃) δ 3.98 (s, 3H),6.77 (m, 1H), 7.16 (m, 1H), 8.98 (s, 1H).

Step 4. Synthesis of 4-fluoro-1,3-benzothiazol-7-ol (C14) To a solutionof 4-fluoro-7-methoxy-1,3-benzothiazole (C13) (10.50 g, 57.30 mmol) indichloromethane (250 mL) was added aluminum chloride (30.56 g, 229.2mmol) in one portion at room temperature. The reaction mixture wasstirred for 12 hours and additional aluminum chloride (30.56 g, 229.2mmol) was added. After another 12 hours, the reaction mixture was pouredinto ice water (1.0 L). The resulting precipitate was collected byfiltration, washed with water, and with 1:1 dichloromethane/hexanes toafford the title compound as a yellow solid. Yield: 6.60 g, 39.0 mmol,68%. Melting point: 165-167° C. LCMS m/z 170.4 (M+1). ¹H NMR (300 MHz,DMSO-d₆) δ 6.82 (m, 1H), 7.21 (m, 1H), 9.37 (s, 1H), 10.57 (s, 1H).

Step 5. Synthesis of 3-amino-4-fluoro-2-sulfanylphenol (C15) A solutionof 4-fluoro-1,3-benzothiazol-7-ol (C14) (2.02 g, 11.93 mmol) in ethanol(20 mL) was treated with hydrazine monohydrate (12.7 mL, 167 mmol) andstirred for at 80° C. for 1 hour. The reaction was concentrated in vacuoand used directly in the following step.

Step 6. Synthesis of 4-fluoro-2-(trifluoromethyl)-1,3-benzothiazol-7-ol(P6). A mixture containing crude 3-amino-4-fluoro-2-sulfanylphenol (C15)(Step 1) and polyphosphoric acid trimethylsilyl ester (10 mL) intrifluoroacetic acid (20 mL) was stirred at 95° C. for 18 hours. Aftercooling to room temperature the reaction was treated with saturatedaqueous sodium bicarbonate solution and extracted with dichloromethane(3×10 mL). The combined organic layers were dried over magnesium sulfateand concentrated in vacuo. Purification via silica gel chromatography(Gradient: 0% to 30% tert-butyl methyl ether in heptanes) afforded thetitle compound as a solid. Yield: 1.66 g, 7.0 mmol, 59%. GCMS m/z 237(M⁺). ¹H NMR (400 MHz, CD₃OD) δ 6.90 (dd, J=8.7, 3.3 Hz, 1H), 7.21 (dd,J=10.2, 8.7 Hz, 1H).

Preparation 7 2-(3,3-Difluorocyclobutyl)-4-fluorophenol (P7)

Step 1. Synthesis of 2-ethenyl-4-fluorophenol (C16). Nitrogen wasbubbled through a mixture of 2-bromo-4-fluorophenol (1.6 g, 8.38 mmol),vinylboronic anhydride pyridine complex (95%, 806 mg, 3.35 mol) andpotassium carbonate (1.17 g, 8.38 mmol) in 1,2-dimethoxyethane (15 mL)for 30 minutes. To this mixture was added palladiumtetrakis(triphenylphosphine) (97.2 mg, 0.084 mmol). The reaction wasallowed to stir at 90° C. for 16 hours. Water (50 mL) was added, and themixture was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with aqueous sodium hydroxide solution (1 N,100 mL) and saturated aqueous sodium chloride solution (100 mL), driedover magnesium sulfate and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 30% ethyl acetate inheptanes) afforded the title compound as a white solid. Yield: 1.03 g,7.46 mmol, 89%. ¹H NMR (400 MHz, CDCl₃) δ 4.91 (br s, 1H), 5.41 (dd,J=11.1, 1.0 Hz, 1H), 5.74 (dd, J=17.6, 1.0 Hz, 1H), 6.74 (dd, J=8.8, 4.7Hz, 1H), 6.82-6.95 (m, 2H), 7.10 (dd, J=9.5, 3.0 Hz, 1H).

Step 2. Synthesis of benzyl 2-ethenyl-4-fluorophenyl ether (C17). Amixture of 2-ethenyl-4-fluorophenol (C16) (1.03 g, 7.46 mmol) andpotassium carbonate (3.12 g, 22.4 mmol) in acetone (35 mL) was treatedwith benzyl bromide (1.78 mL, 14.9 mmol) and stirred at reflux for 3hours. The mixture was concentrated in vacuo, ethyl acetate (100 mL) wasadded and the mixture was washed with water (2×50 mL) and saturatedaqueous sodium chloride solution (50 mL). The organic layer was driedover magnesium sulfate, and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane)afforded the title compound as a colorless oil. Yield: 1.64 g, 7.23mmol, 97%. GCMS m/z 228 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 5.08 (s, 2H),5.33 (dd, J=11.1, 1.0 Hz, 1H), 5.76 (dd, J=17.8, 1.0 Hz, 1H), 6.85-6.95(m, 2H), 7.11 (ddd, J=17.8, 11.1, 1.5 Hz, 1H), 7.23 (dd, J=9.4, 2.9 Hz,1H), 7.33-7.48 (m, 5H).

Step 3. Synthesis of3-[(2-(benzyloxy)-5-fluorophenyl]-2,2-dichlorocyclobutanone (C18).Zinc-copper couple (1.71 g, 13.1 mmol) was added to a solution of benzyl2-ethenyl-4-fluorophenyl ether (C17) (1.0 g, 4.38 mmol) in diethyl ether(15 mL). To this mixture was added drop-wise a mixture of phosphorusoxychloride (446 μL, 4.82 mmol) and trichloroacetyl chloride (978 μL,8.76 mmol) in diethyl ether (5 mL). The mixture was stirred at 40° C.for 2 hours, cooled to room temperature and stirred for an additional 18hours. The solution was filtered through Celite, and the filtrate waswashed with water (2×100 mL) and saturated aqueous sodium chloridesolution (100 mL), dried over magnesium sulfate and concentrated invacuo to afford the title compound as a colorless oil. Yield: 1.4 g,4.13 mmol, 94%. ¹H NMR (400 MHz, CDCl₃) δ 3.57 (dd, half of ABX pattern,J=18.0, 10.5 Hz, 1H), 3.65 (dd, half of ABX pattern, J=18.0, 9.4 Hz,1H), 4.49 (dd, J=10.1, 9.8 Hz, 1H), 5.14 (AB quartet, J_(AB)=12.0 Hz,Δν_(AB)=12.2 Hz, 2H), 6.91-6.95 (m, 2H), 7.01 (ddd, J=9.0, 7.8, 2.9 Hz,1H), 7.32-7.44 (m, 3H), 7.45-7.49 (m, 2H).

Step 4. Synthesis of 3-[(2-(benzyloxy)-5-fluorophenyl]cyclobutanone(C19). A mixture of3-[2-(benzyloxy)-5-fluorophenyl]-2,2-dichlorocyclobutanone (C18) (1.4 g,4.14 mmol) and zinc dust (1.08 g, 16.5 mmol) in acetic acid (25 mL) wasstirred at room temperature for 2 hours and then at 100° C. for 1.25hours. The mixture was filtered through Celite, and the filtrate waswashed with water (50 mL) and saturated aqueous sodium chloride solution(50 mL), dried over magnesium sulfate and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 0% to 30% ethylacetate in heptanes) afforded the title compound as a colorless oil.Yield: 674 mg, 2.49 mmol, 60%. LCMS m/z 179.4 [M-(C₇H₇)]. ¹H NMR (400MHz, CDCl₃) δ 3.22-3.31 (m, 2H), 3.36-3.46 (m, 2H), 3.75-3.85 (m, 1H),5.08 (s, 2H), 6.87-6.95 (m, 2H), 6.99 (dd, J=9.2, 2.7 Hz, 1H), 7.33-7.44(m, 5H).

Step 5. Synthesis of benzyl 2-(3,3-difluorocyclobutyl)-4-fluorophenylether (C20). A solution of 3-[2-(benzyloxy)-5-fluorophenyl]cyclobutanone(C19) (600 mg, 2.22 mmol) in dichloromethane (20 mL) cooled to −78° C.was treated with (diethylamino)sulfur trifluoride (753 mg, 4.44 mmol)over a period of 5 minutes. The mixture was stirred at −78° C. for 30minutes, whereupon it was allowed to warm to room temperature andstirring was continued for 16 hours. The mixture was cooled to −78° C.and a saturated aqueous sodium bicarbonate solution (10 mL) was added.The mixture was allowed to warm to room temperature and additionalsaturated aqueous sodium bicarbonate solution (50 mL) was added,followed by extraction with dichloromethane (2×50 mL). The combinedorganic layers were washed with saturated aqueous sodium chloridesolution (50 mL), dried over magnesium sulfate, and concentrated invacuo. Purification via silica gel chromatography (Gradient: 0% to 25%ethyl acetate in heptanes) afforded the desired title compound as acolorless oil. Yield: 315 mg, 108 mmol, 48%. GCMS m/z 292 (M⁺). ¹H NMR(400 MHz, CDCl₃) δ 2.58-2.73 (m, 2H), 2.90-3.03 (m, 2H), 3.53-3.64 (m,1H), 5.06 (s, 2H), 6.83-6.94 (m, 3H), 7.34-7.45 (m, 5H).

Step 6. Synthesis of 2-(3,3-difluorocyclobutyl)-4-fluorophenol (P7). Amixture of benzyl 2-(3,3-difluorocyclobutyl)-4-fluorophenyl ether (C20)(60 mg, 0.20 mmol) in ethanol (15 mL) was treated with palladium (50 mg,0.47 mmol) and shaken on a Parr hydrogenator (50 psi) at roomtemperature for 2 hours. The mixture was filtered through Celite andconcentrated in vacuo to afford the title compound as a yellow oil.Yield: 20 mg, 0.065 mmol, 100%. GCMS m/z 202 (M⁺). ¹H NMR (400 MHz,CDCl₃) δ 2.60-2.78 (m, 2H), 2.92-3.07 (m, 2H), 3.46-3.58 (m, 1H),6.61-6.95 (m, 3H).

Preparation 82-[2-(2-Bromophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P8)

Step 1. Synthesis of 1-bromo-2-(2-bromoethoxy)benzene (C21). Asuspension of 2-bromophenol (3.50 g, 20.23 mmol), 1,2-dibromoethane(19.00 g, 101 mmol), and potassium carbonate (7.06 g, 2.92 mmol) inacetonitrile (50 mL) was heated to 80° C. After heating overnight, thereaction mixture was cooled to room temperature, diluted with ethylacetate and washed with water and saturated aqueous sodium chloridesolution. The organic layer was dried over magnesium sulfate, filteredand the filtrate was concentrated in vacuo to afford the title compoundas a clear oil. Yield: 6.36 g, 100%. ¹H NMR (400 MHz, CDCl₃) δ 3.69 (dd,J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.7, 6.4 Hz, 2H), 6.87-6.94 (m, 2H),7.25-7.30 (m, 1H), 7.56 (dd, J=7.9, 1.6 Hz, 1H).

Step 2. Synthesis of 2-{[2-(2-bromophenoxy)ethyl]amino}ethanol (C22). Asolution of 1-bromo-2-(2-bromoethoxy)benzene (C21) (5.66 g, 20.22 mmol)and 2-aminoethanol (12.30 g, 202 mmol) in 2-propanol (50 mL) was heatedto 80° C. After heating overnight, the reaction mixture was cooled toroom temperature and concentrated in vacuo. The resulting residue wastaken up in dichloroethane and washed with saturated aqueous sodiumbicarbonate solution and water. The organic layer was dried overmagnesium sulfate, filtered and the filtrate was concentrated in vacuoto afford the title compound as a clear yellow oil. Yield: 5.12 g, 20.18mmol, 97%. LCMS m/z 259.9 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 2.88 (dd,J=5.3, 5.1 Hz, 2H), 3.08 (dd, J=5.1, 5.1 Hz, 2H), 3.67 (dd, J=5.3, 5.3Hz, 2H), 4.14 (dd, J=5.1, 5.1 Hz, 2H), 6.85 (ddd, J=7.6, 7.6, 1.3 Hz,1H), 6.91 (dd, J=8.2, 1.2 Hz, 1H), 7.26 (ddd, J=8.2, 7.6, 1.5 Hz, 1H),7.54 (dd, J=8.0, 1.6 Hz, 1H).

Step 3. Synthesis of2-[2-(2-bromophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P8). A mixture of compound P1 (1.5 g, 5.0 mmol),2-{[2-(2-bromophenoxy)ethyl]amino}ethanol (C22) (1.95 g, 7.5 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 6.46 g, 12 mmol) andN,N-diisopropylethylamine (3.5 g, 27 mmol) in dichloromethane (50 mL)was stirred for 24 hours. The reaction was poured into water and theaqueous phase was extracted with dichloromethane (2×100 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was treated with ethyl acetate (10mL), filtered and the collected solid was washed with ethyl acetate toafford the title compound as a yellow solid. Yield: 1.5 g, 3.4 mmol,68%. LCMS m/z 442.9 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 2.15 (s, 3H),3.88-3.96 (m, 4H), 4.24-4.30 (m, 4H), 6.90 (dd, J=8, 8 Hz, 1H), 7.08 (d,J=7.8 Hz, 1H), 7.15 (br d, J=8 Hz, 1H), 7.34 (dd, J=8, 8 Hz, 1H), 7.40(br s, 1H), 7.58 (br d, J=8 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 8.25 (s,1H).

Preparation 9 2-(Trifluoromethyl)-1,3-benzothiazol-7-ol (P9)

Step 1. Synthesis of 2-bromo-3-methoxyaniline (C23). Iron (1.94 g, 34mmol) was added to a solution of 2-bromo-1-methoxy-3-nitrobenzene (2.50g, 10.77 mmol) in ethanol (18 mL) and concentrated hydrochloric acid (1mL), and the reaction was heated at reflux for 1.5 hours. The mixturewas cooled to room temperature, filtered through Celite and concentratedin vacuo to afford the title compound as a solid. Yield: 2.57 g, 10.77mmol, 100%. LCMS m/z 202.1 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 3.77 (s,3H), 6.30 (d, J=8.0 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0,8.0 Hz, 1H).

Step 2. Synthesis ofN-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroacetamide (C24).Trifluoroacetic anhydride (3.0 mL, 22 mmol) was added to a solution of2-bromo-3-methoxyaniline (C23) (2.57 g, 10.77 mmol) and triethylamine(4.51 mL, 32.3 mmol) in dichloromethane (30 mL) at −78° C. The reactionwas allowed to warm to room temperature and stirring was continued for18 hours, whereupon the mixture was poured into water (40 mL) andextracted with dichloromethane (2×20 mL). The combined organic layerswere dried over sodium sulfate and concentrated in vacuo. Purificationvia silica gel chromatography (Gradient: 0% to 30% methyl tert-butylether in hexanes) afforded the title compound as a colorless solid.Yield: 2.97 g, 9.96 mmol, 92%. GCMS m/z 297, 299 (M⁺). ¹H NMR (400 MHz,CDCl₃) δ 3.94 (s, 3H), 6.81 (dd, J=8.4, 1.2 Hz, 1H), 7.35 (dd, J=8.4,8.3 Hz, 1H), 7.97 (dd, J=8.3, 1.3 Hz, 1H), 8.59 (br s, 1H).

Step 3. Synthesis ofN-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroethanethioamide (C25). Asolution of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroacetamide (C24)(776 mg, 2.6 mmol) and Lawesson's reagent (1.07 g, 2.6 mmol) in1,4-dioxane (13 mL) was heated to 135° C. overnight. The mixture wascooled to room temperature, filtered, and concentrated in vacuo.Purification via silica get chromatography (Gradient: 0% to 20% ethylacetate in heptanes) afforded the title compound as an oil. Yield: 839mg, 2.60 mmol, quantitative. LCMS m/z 314.0 (M+1). ¹H NMR (400 MHz,CDCl₃) δ 3.95 (s, 3H), 6.92 (dd, J=8.3, 1.1 Hz, 1H), 7.39 (dd, J=8.4,8.3 Hz, 1H), 8.28 (dd, J=8.2, 0.8 Hz, 1H), 9.75 (br s, 1H).

Step 4. Synthesis of 7-methoxy-2-(trifluoromethyl)-1,3-benzothiazole(C26). To a solution ofN-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroethanethioamide (C25) (748mg, 2.38 mmol) in 1,2-dimethoxyethane (11.9 mL) was added1,10-phenanthroline (88.4 mg, 0.48 mmol), cesium carbonate (1.55 g, 4.76mmol), and copper iodide (45.3 mg, 0.24 mmol). Nitrogen was bubbledthrough the reaction for 30 minutes and the reaction was heated to 80°C. for 48 hours. The mixture was cooled to room temperature, filteredand concentrated in vacuo. Purification via silica gel chromatography(Gradient: 0% to 30% diethyl ether in hexanes) afforded the titlecompound as a colorless solid. Yield: 398 mg, 1.71 mmol, 72%. GCMS m/z233 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 3H), 6.97 (br d, J=7.9 Hz,1H), 7.56 (dd, J=8.3, 8.0 Hz, 1H), 7.82 (dd, J=8.3, 0.6 Hz, 1H).

Step 5. Synthesis of 2-(trifluoromethyl)-1,3-benzothiazol-7-ol (P9). Asolution of 7-methoxy-2-(trifluoromethyl)-1,3-benzothiazole (C26) (398mg, 1.71 mmol) in dichloromethane (10 mL) at −78° C. was treated withboron tribromide (1 M in dichloromethane, 3.41 mL, 3.41 mmol), warmed toroom temperature and stirred for 18 hours. Methanol (3.0 mL) was addedto the mixture at −78° C. and the mixture was warmed to roomtemperature. Water (30 mL) was added and the mixture was extracted withdichloromethane (2×10 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. Purification via silica gelchromatography (Gradient: 0% to 20% methyl tert-butyl ether in heptanes)afforded the title compound as a colorless solid. Yield: 251 mg, 1.15mmol, 67%. GCMS m/z 219 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 6.44 (br s, 1H),6.95 (d, J=7.8 Hz, 1H), 7.47 (dd, J=8.2, 8.0 Hz, 1H), 7.82 (d, J=8.2 Hz,1H).

Preparation 10 2′-Methyl-2-oxo-1,2-dihydro-3,4′-bipyridine-6-carboxylicacid, hydrochloride salt (P10)

Step 1. Synthesis of 3-bromo-2-chloropyridine 1-oxide (C27). A solutionof 3-bromo-2-chloropyridine (50 g, 0.26 mol) and 3-chloroperoxybenzoicacid (70-75% wet with water; 67.3 g, 0.39 mol) in 1,2-dichloroethane(600 mL) was heated under reflux for 7 hours. The reaction was thenconcentrated under reduced pressure to an approximate volume of 200 mLand purified by chromatography on silica gel (Gradient: 80% to 100%ethyl acetate in heptane, followed by 5% to 10% methanol in ethylacetate) to yield the title compound as a brown solid. Yield: 32.9 g,0.158 mol, 61%. LCMS m/z 210.0 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.09(dd, J=7.8, 6.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 8.33 (d, J=6.4 Hz, 1H).

Step 2. Synthesis of 5-bromo-6-chloropyridine-2-carbonitrile (C28).Trimethylsilyl cyanide (19 mL, 0.15 mol) was added to a stirred solutionof 3-bromo-2-chloropyridine 1-oxide (C27) (31.6 g, 0.152 mol) andtriethylamine (63.4 mL, 0.46 mol) in acetonitrile (400 mL). The reactionmixture was heated to 50° C. for 2 hours. It was then cooled to roomtemperature and additional trimethylsilyl cyanide (19 mL, 0.15 mol) wasadded. After the reaction mixture was heated at 50° C. for 1.5 hours, afinal portion of trimethylsilyl cyanide (28.5 mL, 0.23 mol) was addedand the reaction was heated at reflux for 3 days. After dilution withdichloromethane (2 L), the reaction was washed with saturated aqueoussodium bicarbonate solution (800 mL), then with water (1 L), dried overmagnesium sulfate and concentrated in vacuo. Purification via silica gelchromatography (Gradient: 20% to 25% ethyl acetate in heptane) affordedthe title compound as a yellow solid. Yield: 14.92 g, 68.6 mmol, 45%.

The reaction was also performed using the acylating agentdimethylcarbamoyl chloride. A solution of dimethylcarbamoyl chloride(12.9 mL, 0.14 mol) in dichloromethane (23 mL) was added drop-wise to astirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (11.23 g,53.9 mmol) and trimethylsilyl cyanide (17.5 mL, 0.14 mol) indichloromethane (200 mL). The reaction mixture was heated under refluxfor 3 days, then diluted with dichloromethane (450 mL) and washed withsaturated aqueous sodium bicarbonate solution (2×200 mL), then withwater (200 mL), dried over magnesium sulfate and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 15% to 20% ethylacetate in heptane) provided the title compound, contaminated withdimethylcarbamoyl cyanide (12.73 g, 100%) as an off-white solid. Theimpurity was reduced by repeatedly washing with aqueous sodium hydroxidesolution (2 N) and a second chromatography on silica gel. Although theimpurity could not be completely removed, the material was used in thenext step without any detrimental effects. Yield: 7.83 g, 36.0 mmol,67%. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8Hz, 1H).

Step 3. Synthesis of methyl 5-bromo-6-methoxypyridine-2-carboximidoate(C29). Sodium hydride (60% dispersion in mineral oil, 3.57 g, 93.8 mmol)was added portion-wise over a 20 minute period to a stirred solution ofmethanol (7.1 mL) in tetrahydrofuran (123 mL) under argon; the reactionwas then stirred for an additional 55 minutes. A solution of5-bromo-6-chloropyridine-2-carbonitrile (C28) (8.16 g, 37.5 mmol) intetrahydrofuran (71 mL) was then added drop-wise and the reactionmixture was stirred for 18 hours. After being quenched with saturatedaqueous ammonium chloride solution (200 mL), the mixture was extractedwith ethyl acetate (2×400 mL). The combined organic layers were washedwith saturated aqueous sodium chloride solution (200 mL), dried overmagnesium sulfate and concentrated in vacuo to give the crude titlecompound (9.42 g, quantitative) as an orange solid, which was used inthe next step without further purification, as it was found to beunstable on silica gel. LCMS m/z 247.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ3.99 (s, 3H), 4.09 (s, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz,1H).

Step 4. Synthesis of methyl 5-bromo-6-methoxypyridine-2-carboxylate(C30). A stirred solution of methyl5-bromo-6-methoxypyridine-2-carboximidoate (C29) (9.42 g, 38.4 mmol) inmethanol (66 mL) and concentrated hydrochloric acid (6.6 mL) was heatedunder reflux for 18 hours. The reaction was concentrated to drynessunder reduced pressure. The resulting solid was dissolved indichloromethane (500 mL) and washed with saturated aqueous sodiumbicarbonate solution (250 mL). The aqueous phase was extracted withdichloromethane (200 mL), and the combined organics were washed withwater (250 mL), with saturated aqueous sodium chloride solution (250mL), dried over magnesium sulfate and concentrated under reducedpressure to provide the title compound. The reaction was repeated onadditional material (1.65 g, 6.73 mmol), worked up in a similar manner,combined with the first reaction, and purified by silica gelchromatography (Eluant: 10% ethyl acetate in heptane) to provide thetitle compound as a yellow solid. Yield: 4.48 g, 18.2 mmol, 40%. LCMSm/z 246.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 3.97 (s, 3H), 4.11 (s, 3H),7.59 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).

Step 5. Synthesis of methyl6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(C31). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (740 mg, 0.91 mmol) was added in oneportion to a degassed mixture of methyl5-bromo-6-methoxypyridine-2-carboxylate (C30) (7.42 g, 30.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (9.19 g, 36.2mmol) and potassium acetate (8.88 g, 90.5 mmol) in dioxane (150 mL) atroom temperature under argon and the reaction was heated at 100° C. for18 hours. The mixture was cooled to room temperature, filtered throughCelite, washed with ethyl acetate (400 mL) and concentrated in vacuo.Silica gel chromatography (Gradient: 15% to 35% ethyl acetate inheptane) afforded the title compound as a colorless oil, whichsolidified on standing to form a white crystalline solid. Yield: 7.14 g,24.4 mmol, 81%. LCMS m/z 212.1 (M for boronic acid+1). ¹H NMR (400 MHz,CDCl₃) δ 1.37 (s, 12H), 3.97 (s, 3H), 4.06 (s, 3H), 7.67 (d, J=7.3 Hz,1H), 8.09 (d, J=7.3 Hz, 1H). A second crop of material (1.13 g, 13%) wasalso obtained from the purification; this contained minor impurities byNMR analysis.

Step 6. Synthesis of methyl2-methoxy-2′-methyl-3,4′-bipyridine-6-carboxylate (C32). Degassed1,2-dimethoxyethane (60 mL) and water (0.5 mL) were added to a flaskcharged with 4-bromo-2-methylpyridine (1.20 g, 6.98 mmol), methyl6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(C31) (3.07 g, 10.5 mmol), potassium phosphate (4.44 g, 20.9 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol). Themixture was heated to 80° C. for 18 hours, then cooled to roomtemperature and concentrated in vacuo. Silica gel chromatography(Eluant: ethyl acetate) provided a solid, which was triturated twicewith a 1:5 mixture of ethyl acetate and heptane to provide the titlecompound as a white solid. Yield: 1.68 g, 6.50 mmol, 93%. LCMS m/z 259.1(M+1). ¹H NMR (400 MHz, CDCl₃) δ 2.63 (s, 3H), 4.00 (s, 3H), 4.09 (s,3H), 7.32 (br d, J=5.5 Hz, 1H), 7.36 (br s, 1H), 7.79 (AB quartet,J_(AB)=7.3 Hz, Δν_(AB)=24.1 Hz, 2H), 8.57 (d, J=5.0 Hz, 1H).

Step 7. Synthesis of2′-methyl-2-oxo-1,2-dihydro-3,4′-bipyridine-6-carboxylic acid,hydrochloride salt (P10). Methyl2-methoxy-2′-methyl-3,4′-bipyridine-6-carboxylate (C32) (1.25 g, 4.84mmol) was dissolved in dioxane (40 mL) and aqueous hydrochloric acid(37%, 40 mL), and heated to reflux for 18 hours. The reaction was cooledand concentrated to dryness, azeotroped with toluene and methanol andagain concentrated to dryness. This process was repeated twice and theresulting solid was triturated three times with a 1:2:0.5 mixture ofethyl acetate/heptane/methanol to give the title compound as a yellowsolid. Yield: 1.30 g, 4.87 mmol, quantitative. LCMS m/z 231.1 (M+1). ¹HNMR (400 MHz, DMSO-d₆) δ 2.76 (s, 3H), 7.08 (d, J=7.3 Hz, 1H), 8.24 (d,J=7.3 Hz, 1H), 8.31-8.38 (m, 2H), 8.76 (d, J=6.0 Hz, 1H), 12.2 (v br s,1H).

Preparation 114-(4-Chloro-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrochloride salt (P11)

Step 1. Synthesis of 4-chloro-1H-imidazole (C33). To a solution of1H-imidazole (22.1 g, 324 mmol) in N,N-dimethylformamide at 0° C. wasadded drop-wise (over 4 hours) a solution of N-chlorosuccinimide (25 g,190 mmol) in N,N-dimethylformamide (total solvent, 160 mL). The reactionwas stirred at 0° C. for 1 hour, whereupon water (200 mL) was added at0° C. The mixture was extracted with ethyl acetate (3×50 mL), and thecombined organic layers were concentrated in vacuo. Purification wascarried out using supercritical fluid chromatography (Column: PrincetonCyano, 5 μm; Eluant: 15:85 methanol/carbon dioxide). The resultingmaterial was purified again, using silica gel chromatography (Mobilephase A: ethyl acetate; Mobile phase B: [20% (2 M ammonia in methanol)in dichloromethane]; Gradient: 0% to 10% B) to afford the title compoundas a white solid. Yield: 2.45 g, 23.9 mmol, 12%. GCMS m/z 102, 104 (M⁺).¹H NMR (400 MHz, CDCl₃) δ 7.00 (d, J=1.2 Hz, 1H), 7.57 (br s, 1H), 11.3(v br s, 1H).

Step 2. Synthesis of ethyl4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34).1,1-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to asolution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared inanalogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate(C30) in Preparation 10; 254 mg, 0.97 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol),and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). Thereaction was stirred at 85° C. for 6 hours, whereupon it was allowed tocool to room temperature. Dichloromethane was added, and the resultingmixture was washed with saturated aqueous sodium bicarbonate solution,dried over magnesium sulfate, and concentrated in vacuo to affordintermediate ethyl5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate.To a solution of ethyl5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate(crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reactionwas stirred at ambient temperature overnight. The mixture was heated to50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol)was added. The reaction was heated to reflux for 2 hours and was thenfiltered through Celite. The Celite pad was washed with methanol, andthe combined filtrate and washings were concentrated in vacuo.Purification was carried out twice via silica gel chromatography(Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethylacetate in heptane), affording the title compound as a white solid.Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). ¹H NMR (400 MHz,CDCl₃) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H),7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84(d, J=7.8 Hz, 1H).

Step 3. Synthesis of4-(4-chloro-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, hydrochloride salt (P11). To a solution of4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34)(20.9 mg, 0.074 mmol) in acetic acid (0.5 mL) was added concentratedhydrochloric acid and the reaction was stirred at 95° C. for 18 hours.Removal of solvent in vacuo afforded the title compound as a whitesolid. Yield: 20.4 mg, 0.074 mmol, 100%. LCMS m/z 240.3 (M+1). ¹H NMR(400 MHz, CD₃OD) δ 7.19 (d, J=7.5 Hz, 1H), 7.94-7.98 (m, 2H), 9.01-9.05(m, 1H).

Preparation 12 (2S)-2-[(tert-Butoxycarbonyl)amino]propylmethanesulfonate (P12)

Methanesulfonyl chloride (13.2 mL, 170 mmol) was added to a 0° C.solution of tert-butyl [(2S)-1-hydroxypropan-2-yl]carbamate (28.4 g, 162mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (350 mL),and the reaction mixture was allowed to stir for 30 minutes. Afteraqueous ammonium chloride solution was added to the reaction mixture,the aqueous layer was extracted with dichloromethane, and the combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting sticky white solid was slurriedwith diethyl ether (100 mL), stirred for 10 minutes, and filtered toafford the product as a white solid. Yield: 28.8 g, 114 mmol, 70%. Thefiltrate was concentrated under reduced pressure and recrystallized fromdiethyl ether (the hot mixture was filtered through Celite beforecrystallization) to provide additional product as a white solid. Yield:11.66 g, 45.63 mmol, combined yield 98%. ¹H NMR (400 MHz, CDCl₃) δ 1.24(d, J=7.0 Hz, 3H), 1.45 (s, 9H), 3.04 (s, 3H), 3.91-4.04 (br m, 1H),4.16 (dd, half of ABX pattern, J=10.1, 4.2 Hz, 1H), 4.19-4.28 (br m,1H), 4.62 (br s, 1H).

Preparation 13(2S)-1-[4-Fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine(P13)

Step 1. Synthesis of4-fluoro-1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene (C42).Dichlorobis(triphenylphosphine)palladium(II) (98%, 530 mg, 0.74 mmol)was added to a mixture of (5-fluoro-2-methoxyphenyl)boronic acid (10.0g, 58.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (6.75 mL, 65.0 mmol)and potassium carbonate (16.3 g, 118 mmol) in tetrahydrofuran (100 mL)and water (30 mL), and the reaction mixture was stirred for 18 hours atroom temperature. The aqueous layer was extracted with diethyl ether(100 mL), and the combined organic layers were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated in vacuo, while keeping the bath temperatureat <30° C. Pentane (200 mL) was added, the mixture was filtered, and thefiltrate was concentrated under reduced pressure; the residue wassubjected to silica gel chromatography (Eluent: pentane) to afford theproduct as a colorless oil. Yield: 9.08 g, 41.2 mmol, 70%. ¹H NMR (400MHz, CDCl₃) δ 3.80 (s, 3H), 5.69-5.70 (m, 1H), 6.12-6.13 (m, 1H), 6.88(dd, J=9.0, 4.5 Hz, 1H), 6.98 (br dd, J=8.8, 3.1 Hz, 1H), 7.05 (ddd,J=9.0, 7.8, 3.1 Hz, 1H).

Step 2. Synthesis of4-fluoro-1-methoxy-2-(1,1,1-trifluoropropan-2-yl)benzene (C43).4-Fluoro-1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene (C42) (82 g,370 mmol) was split into four batches; each batch was dissolved inmethanol (200 mL), treated with 10% palladium on carbon (1 g, 10 mmol)and hydrogenated at 50 psi for 15 minutes. After careful filtrationthrough Celite and rinsing of the filter pad with methanol, the fourfiltrates were combined and concentrated in vacuo, keeping the bathtemperature at <25° C. The residue was dissolved in dichloromethane,filtered through Celite, and concentrated under reduced pressure,providing the product as a light yellow oil. Yield: 71.0 g, 320 mmol,86%. ¹H NMR (400 MHz, CDCl₃) η1.42 (d, J=7.2 Hz, 3H), 3.83 (s, 3H),4.06-4.19 (m, 1H), 6.84 (dd, J=9.0. 4.5 Hz, 1H), 6.98 (ddd, J=9.0, 7.8,3.1 Hz, 1H), 7.06-7.11 (m, 1H).

Step 3. Synthesis of 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol(C44). Boron tribromide (19.1 mL, 198 mmol) was added to a −78° C.solution of 4-fluoro-1-methoxy-2-(1,1,1-trifluoropropan-2-yl)benzene(C43) (20.0 g, 90.0 mmol) in dichloromethane (400 mL). The cooling bathwas removed and the reaction mixture was allowed to warm to roomtemperature over 66 hours. It was then cooled in an ice bath and treateddrop-wise with water (50 mL) while venting into an aqueous potassiumcarbonate trap. When the vigorous reaction had subsided, additionalwater (300 mL) was added, and the mixture was stirred until all thesolids had dissolved. The aqueous layer was extracted withdichloromethane (200 mL), and the combined organic layers were driedover magnesium sulfate, filtered, and concentrated under reducedpressure, while keeping the water bath between 23° C. and 35° C. Theproduct was obtained as an oil, which contained some impurities by ¹HNMR assessment; this was used without additional purification. Yield:20.6 g, assumed quantitative. ¹H NMR (400 MHz, CDCl₃), product peaksonly: δ 1.45 (d, J=7.4 Hz, 3H), 3.98-4.12 (m, 1H), 6.74 (dd, J=8.8, 4.5Hz, 1H), 6.85-6.91 (m, 1H), 7.04-7.09 (m, 1H).

Step 4. Synthesis of(2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine(P13). Cesium carbonate (28.6 g, 87.8 mmol) was added to a solution ofcrude 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol (C44) (6.00 g, 28.8mmol) in N,N-dimethylformamide (60 mL). After addition of(2S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (P12) (7.5 g,29.6 mmol), the reaction mixture was heated in a 60° C. oil bath for 30minutes, then treated with additional P12 (7.5 g, 29.6 mmol) and heatedfor 18 hours. At this point, the reaction mixture was allowed to cool toroom temperature, diluted with water (500 mL), and extracted withdiethyl ether (3×150 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The resulting material (11.23 g) was dissolved in dichloromethane (200mL); trifluoroacetic acid (40 mL) was added, and the reaction mixturewas stirred for 1 hour. After removal of solvents in vacuo, the residuewas dissolved in ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution and with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated invacuo. Purification using silica gel chromatography (Eluents: 75% ethylacetate in heptane, then ethyl acetate, then 10% methanol in ethylacetate) afforded the product as a roughly 1:1 mixture of twodiastereomers, as assessed by ¹H NMR. Yield: 5.44 g, 20.5 mmol, 71%.LCMS m/z 266.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ [1.31 (d, J=6.6 Hz) and1.32 (d, J=6.6 Hz), total 3H], 1.41 (d, J=7.2 Hz, 3H), 3.50-3.59 (m,1H), 3.82-4.22 (m, 3H), 6.79-6.84 (m, 1H), 6.92-6.98 (m, 1H), 7.05-7.11(m, 1H). Also obtained was material enriched in the higher R_(f)diastereomer (1.10 g, 4.15 mmol, 14%) and material enriched in the lowerR_(f) diastereomer (324 mg, 1.22 mmol, 4%).

Preparation 147-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione(P14)

N,N-Dimethylformamide (850 mL) was added to a mixture of5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid hydrochloride salt (C3) (65 g, 250 mmol), 1,2-dibromoethane (52.5g, 280 mmol) and cesium carbonate (124 g, 381 mmol), and the reactionmixture was heated to 90° C. for 6 hours. After allowing the reaction tocool to room temperature, the mixture was filtered through Celite, andthe filtrate was concentrated in vacuo. The residue was dissolved indichloromethane (500 mL), washed with saturated aqueous sodium chloridesolution (100 mL), washed with water (50 mL), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting solid was washed with acetonitrile to provide the product.Yield: 46.5 g, 190 mmol, 76%. ¹H NMR (400 MHz, CDCl₃) δ 2.30 (d, J=0.8Hz, 3H), 4.38-4.42 (m, 2H), 4.66-4.70 (m, 2H), 7.15-7.17 (m, 1H), 7.43(AB quartet, J_(AB)=7.7 Hz, Δν_(AB)=33.4 Hz, 2H), 8.33 (d, J=1.4 Hz,1H).

Preparation 15 1-Fluoro-4-nitro-2-(pentafluoro-λ⁶-sulfanyl)benzene (P15)

A mixture of 1-fluoro-2-(pentafluoro-λ⁶-sulfanyl)benzene (2.00 g, 9.00mmol) and sulfuric acid (4 mL) was cooled in an ice bath. Nitric acid (4mL) was added to the reaction mixture; after 5 minutes, the cooling bathwas removed and stirring was continued at room temperature for 3 hours.The reaction mixture was then poured into ice (150 mL), and theresulting mixture was extracted with diethyl ether (2×75 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo to provide an oil. After addition of a seedcrystal, the product was obtained as a solid. Yield: 1.99 g, 7.45 mmol,83%. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (br dd, J=10, 9 Hz, 1H), 8.46 (brddd, J=9.1, 3, 3 Hz, 1H), 8.72 (dd, J=5.8, 2.7 Hz, 1H).

EXAMPLES Example 12-{2-[4-Fluoro-2-(trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(1)

Step 1. Synthesis of1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (C35). A mixtureof 4-fluoro-2-(trifluoromethyl)phenol (1.05 g, 5.83 mmol),2-bromoethanol (0.62 mL, 8.7 mmol) and triphenylphosphine (2.29 g, 8.73mmol) in tetrahydrofuran (20 mL) was stirred for 5 minutes. Diisopropylazodicarboxylate (94%, 1.84 mL, 8.71 mmol) was then added drop-wise over20 minutes, and the reaction was stirred at room temperature for 16hours. Water (50 mL) was added, and the mixture was extracted withdichloromethane (2×75 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution (50 mL), dried over magnesiumsulfate, and concentrated in vacuo. Purification via silica gelchromatography (Gradient: 0% to 10% ethyl acetate in heptane) affordedthe title compound as a white solid. Yield: 600 mg, 2.09 mmol, 36%. GCMSm/z 286. ¹H NMR (400 MHz, CDCl₃) δ 3.66 (dd, J=6.6, 6.4 Hz, 2H), 4.35(dd, J=6.5, 6.4 Hz, 2H), 6.97 (br dd, J=9.0, 4.1 Hz, 1H), 7.18-7.24 (m,1H), 7.32 (br dd, J=8.3, 3.2 Hz, 1H).

Step 2. Synthesis of2-({2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}amino)ethanol (C36). Amixture of 1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (C35)(600 mg, 2.09 mmol) and 2-aminoethanol (2.20 mL, 52.4 mmol) was heatedto 80° C. for 1.5 hours. The reaction was allowed to cool to roomtemperature, diluted with ethyl acetate (75 mL) and washed with aqueoussodium hydroxide solution (1 N, 4×50 mL). The organic layer was driedover magnesium sulfate and concentrated under reduced pressure toprovide the title compound as a white solid. Yield: 550 mg, 2.06 mmol,99%. LCMS m/z 268.1 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 2.80 (br dd, J=5.5,5.4 Hz, 2H), 3.04 (dd, J=5.4, 5.2 Hz, 2H), 3.68 (br dd, J=5.6, 5.4 Hz,2H), 4.20 (dd, J=5.3, 5.3 Hz, 2H), 7.22 (br dd, J=8.8, 4.2 Hz, 1H),7.30-7.37 (m, 2H).

Step 3. Synthesis of2-{2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(1).5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid, 0.7 hydrobromide salt (P1) (201 mg, 0.729 mmol) and2-({2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}amino)ethanol (C36)(214 mg, 0.801 mmol) were combined with dichloromethane (15 mL) andN,N-diisopropylethylamine (0.508 mL, 2.92 mmol), and the mixture wasstirred for 5 minutes at room temperature.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 857 mg, 2.19 mmol) was added in oneportion, and the reaction was stirred for an additional 16 hours. Water(50 mL) was added, and the mixture was extracted with dichloromethane(3×50 mL). The combined organic layers were washed sequentially withsaturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) andsaturated aqueous sodium chloride solution (50 mL), then dried overmagnesium sulfate and concentrated in vacuo. Purification was carriedout twice using silica gel chromatography (Gradient #1: 0% to 20%methanol in dichloromethane; Gradient #2: 0% to 70% [10% 2 N ammonia inmethanol/90% ethyl acetate] in ethyl acetate) to afford the titlecompound as a white solid. Yield: 268 mg, 0.595 mmol, 82%. LCMS m/z451.0 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 2.24 (d, J=0.9 Hz, 3H), 3.90-3.95(m, 2H), 4.01 (dd, J=5.1, 5.1 Hz, 2H), 4.32-4.37 (m, 4H), 7.21-7.26 (m,1H), 7.25 (d, J=7.8 Hz, 1H), 7.30-7.32 (m, 1H), 7.32-7.39 (m, 2H), 7.76(d, J=7.8 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H).

Example 22-{2-[(7-Fluoronaphthalen-1-yl)oxy]ethyl}-7-(2-methyl-1,3-oxazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(2)

Step 1: Synthesis of5-(2-methyl-1,3-oxazol-5-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid(C39).

A. Synthesis of methyl6-methoxy-5-(2-methyl-1,3-oxazol-5-yl)pyridine-2-carboxylate (C37). Amixture of 2-methyl-1,3-oxazole (2.41 g, 29.0 mmol), methyl5-bromo-6-methoxypyridine-2-carboxylate (C30) (1.51 g, 5.81 mmol),potassium carbonate (finely ground, 2.41 g, 17.4 mmol), andallylpalladium chloride dimer (224 mg, 0.58 mmol) in 1,4-dioxane (11.6mL) was heated to 100° C. overnight. The mixture was filtered throughCelite, and the Celite pad was washed with ethyl acetate followed byethanol. The combined filtrate and washings were concentrated in vacuo.Purification via silica gel chromatography (Gradient: 10% to 100% ethylacetate in heptanes) afforded the title compound as a solid. Yield: 267mg, 1.02 mmol, 18%. ¹H NMR (400 MHz, CD₃OD) δ 1.42 (t, J=7.1 Hz, 3H),2.56 (s, 3H), 4.17 (s, 3H), 4.43 (q, J=7.1 Hz, 2H), 7.59 (s, 1H), 7.83(d, J=7.8 Hz, 1H), 8.17 (d, J=7.7 Hz, 1H).

B. Synthesis of6-methoxy-5-(2-methyl-1,3-oxazol-5-yl)pyridine-2-carboxylic acid (C38).To a mixture of methyl6-methoxy-5-(2-methyl-1,3-oxazol-5-yl)pyridine-2-carboxylate (C37) (217mg, 0.87 mmol) in tetrahydrofuran (8.7 mL) and water (2.0 mL) was addedlithium hydroxide (62.8 mg, 2.62 mmol) and the reaction was stirred atroom temperature for 18 hours. To the mixture was added additionallithium hydroxide (62.8 mg, 2.62 mmol) and Amberlite IRC-50 ion-exchangeresin. The mixture was filtered, concentrated in vacuo, and azeotropedthree times with toluene to afford the title compound as a solid. Yield:173 mg, 0.74 mmol, 85%. LCMS m/z 235.2 (M+1). ¹H NMR (400 MHz, CD₃OD) δ2.54 (s, 3H), 4.18 (s, 3H), 7.48 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 8.07(d, J=7.7 Hz, 1H).

C. Synthesis of5-(2-methyl-1,3-oxazol-5-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid(C39). To a solution of6-methoxy-5-(2-methyl-1,3-oxazol-5-yl)pyridine-2-carboxylic acid (C38)(173 mg, 0.74 mmol) in anhydrous acetonitrile (8.2 mL) at 0° C. wasadded sodium iodide (177 mg, 1.18 mmol) and trimethylsilyl chloride (149μL, 1.18 mmol). The mixture was warmed to room temperature, then heatedat reflux for 18 hours. The reaction was quenched with methanol,concentrated in vacuo, and treated with hydrogen chloride (4 M in1,4-dioxane) and pentane. The mixture was filtered to afford the titlecompound as a solid. Yield: 90 mg, 0.41 mmol, 55%. LCMS m/z 221.2 (M+1).

Step 2: Synthesis of2-({2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}amino)ethanol (C41).

A. Synthesis of 1-(2-chloroethoxy)-7-fluoronaphthalene (C40). To asolution of 7-fluoronaphthalen-1-ol (500 mg, 3.08 mmol) in methyl ethylketone (7.71 mL) was added potassium carbonate (682 mg, 4.93 mmol) and1-bromo-2-chloroethane (1.46 mL, 17.0 mmol). The reaction was heated atreflux for 18 hours, whereupon it was allowed to cool to roomtemperature. Saturated aqueous potassium carbonate solution was added,and the mixture was extracted three times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo. Purification via silica gel chromatography (Gradient: 10% to50% ethyl acetate in heptanes) afforded the title compound as an oil.Yield: 429 mg, 1.59 mmol, 52%. ¹H NMR (400 MHz, CDCl₃) δ 3.79 (t, J=6.2Hz, 2H), 4.48 (t, J=6.2 Hz, 2H), 6.84 (d, J=7.6 Hz, 1H), 7.28 (ddd,J=8.9, 8.4, 2.7 Hz, 1H), 7.34 (br dd, J=8.2, 7.7 Hz, 1H), 7.47 (br d,J=8.3 Hz, 1H), 7.80 (dd, J=9.0, 5.7 Hz, 1H), 7.91 (br dd, J=10.6, 2.6Hz, 1H).

B. Synthesis of 2-({2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}amino)ethanol(C41). A solution of 1-(2-chloroethoxy)-7-fluoronaphthalene (C40) (429mg, 1.59 mmol) in N,N-dimethylformamide (8.9 mL) was treated with2-aminoethanol (1.03 mL, 18.6 mmol) and heated to 80° C. for 18 hours.The reaction was cooled to room temperature, treated with saturatedaqueous sodium bicarbonate solution (100 mL) and extracted with ethylacetate (3×75 mL). The combined organic layers were washed with aqueoussodium hydroxide (1 M), dried over sodium sulfate and concentrated invacuo. Purification via silica gel chromatography afforded the titlecompound as a colorless solid. Yield: 194 mg, 0.77 mmol, 48%. ¹H NMR(400 MHz, CDCl₃) δ 2.92-2.97 (m, 2H), 3.19 (dd, J=5.3, 5.1 Hz, 2H),3.69-3.73 (m, 2H), 4.27 (dd, J=5.3, 5.1 Hz, 2H), 6.87 (d, J=7.6 Hz, 1H),7.25-7.30 (m, 1H, assumed; partially obscured by solvent peak), 7.34(dd, J=8.1, 7.7 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.80 (dd, J=9.1, 5.6Hz, 1H), 7.85 (dd, J=10.5, 2.5 Hz, 1H).

Step 3: Synthesis of2-{2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}-7-(2-methyl-1,3-oxazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(2). 5-(2-Methyl-1,3-oxazol-5-yl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid (C39) (45 mg, 0.20 mmol) and2-({2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}amino)ethanol (C41) (55.8 mg,1.1 mmol) were combined with dichloromethane (4 mL) andN,N-diisopropylethylamine (178 μL, 1.02 mmol).O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 97%, 171 mg, 0.45 mmol) was added, and thereaction was stirred at room temperature for 18 hours. Saturated aqueoussodium bicarbonate solution was added and the mixture was extractedthree times with ethyl acetate. The combined organic layers were driedover sodium sulfate and concentrated in vacuo. Purification via silicagel chromatography (Gradient: 50% to 100% ethyl acetate in heptane,followed by elution with 20% methanol in ethyl acetate) was followed byhigh-pressure liquid chromatographic purification (Silica column, 5 μm;Gradient: 5% to 100% ethanol in heptane), to afford the title compoundas a solid. Yield: 10 mg, 0.022 mmol, 11%. LCMS m/z 434.5 (M+1). ¹H NMR(400 MHz, CDCl₃) δ 2.64 (s, 3H), 3.97-4.02 (m, 2H), 4.12-4.16 (m, 2H),4.39-4.47 (m, 4H), 6.85 (d, J=7.6 Hz, 1H), 7.26-7.31 (m, 1H, assumed;partially obscured by solvent peak), 7.31-7.36 (m, 2H), 7.46 (d, J=8.2Hz, 1H), 7.71 (dd, J=10.3, 2.5 Hz, 1H), 7.81 (dd, J=9.0, 5.5 Hz, 1H),7.89 (d, J=7.6 Hz, 1H), 8.00 (s, 1H).

Example 1172-{(2S)-1-[4-Chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(117)

Step 1. Synthesis of2-(5-chloro-2-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (C45). Asolution of 1-(5-chloro-2-methoxyphenyl)-2,2,2-trifluoroethanone (3.00g, 12.6 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C.Methylmagnesium bromide (3 M in diethyl ether, 6.29 mL, 18.9 mmol) wasadded drop-wise over a period of 10 minutes, and the mixture was warmedto 0° C. and stirred at that temperature for 30 minutes. After thereaction had been quenched by addition of saturated aqueous ammoniumchloride solution (10 mL) over a period of 5 minutes, water (50 mL) wasadded, and the resulting mixture was extracted with dichloromethane(3×50 mL). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo to provide the product as acolorless oil containing residual tetrahydrofuran (the molar ratio ofproduct:tetrahydrofuran was 2:1), which was taken to the following stepwithout further purification. Corrected yield: 2.77 g, 10.9 mmol, 86%.GCMS m/z 254 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 1.76 (br s, 3H), 3.94 (s,3H), 5.88 (br s, 1H), 6.94 (d, J=8.8 Hz, 1H), 7.30-7.35 (m, 2H).

Step 2. Synthesis of4-chloro-2-(2-chloro-1,1,1-trifluoropropan-2-yl)-1-methoxybenzene (C46).2-(5-Chloro-2-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (C45) (1.20 g,4.71 mmol) was treated with thionyl chloride (4 mL, 50 mmol), followedby pyridine (19.1 μL, 0.236 mmol). The reaction mixture was heated at40° C. for 16 hours, then poured into a mixture of ice and saturatedaqueous sodium bicarbonate solution. The resulting mixture was extractedwith dichloromethane (3×50 mL), and the combined organic layers weredried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was determined by ¹H NMR to be a mixture ofproduct and an alkene side-product derived from elimination, in aroughly 4:1 ratio; this was used in the following step withoutadditional purification. GCMS m/z 272 (M⁺). ¹H NMR (400 MHz, CDCl₃),product peaks only: δ 2.27 (br s, 3H), 3.86 (s, 3H), 6.90 (d, J=8.8 Hz,1H), 7.33 (dd, J=8.8, 2.5 Hz, 1H), 7.69-7.73 (m, 1H).

Step 3. Synthesis of4-chloro-1-methoxy-2-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (C47).A solution of4-chloro-2-(2-chloro-1,1,1-trifluoropropan-2-yl)-1-methoxybenzene (C46)(derived from the preceding step, <4.71 mmol) in dichloromethane (30 mL)was cooled to −78° C. Trimethylaluminum (2 M in hexanes, 7.32 mL, 14.6mmol) was then added drop-wise over a period of 10 minutes, and thereaction mixture was stirred at −78° C. for 30 minutes. It was thenallowed to warm to room temperature and stirred for 16 hours, at whichtime it was cooled to −78° C. and quenched with water (10 mL). Thereaction mixture was filtered through Celite, and the filter pad waswashed with dichloromethane; the combined filtrates were washed withsaturated aqueous sodium chloride solution, concentrated in vacuo, andpurified using silica gel chromatography (Eluant: hexanes) to afford theproduct as a colorless oil. Yield: 746 mg, 2.95 mmol, 63% over 2 steps.¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 3.83 (s, 3H), 6.86 (d,J=8.8 Hz, 1H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 7.35-7.37 (m, 1H).

Step 4. Synthesis of4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenol (C48). Borontribromide (1 M in dichloromethane, 16.8 mL, 16.8 mmol) was addeddrop-wise over 10 minutes to a −78° C. solution of4-chloro-1-methoxy-2-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (C47)(850 mg, 3.36 mmol) in dichloromethane (10 mL). After stirring at −78°C. for 30 minutes, the reaction mixture was heated to 40° C. and held atthat temperature for 24 hours. The reaction mixture was then cooled to−78° C. and quenched with saturated aqueous sodium bicarbonate solution(10 mL). The pH was adjusted to approximately 5 with aqueoushydrochloric acid, and the mixture was extracted with dichloromethane(3×50 mL). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo. Purification using silicagel chromatography (Gradient: 0% to 20% ethyl acetate in heptane)afforded the product as a colorless oil. Yield: 515 mg, 2.16 mmol, 64%.GCMS m/z 238 (M⁺). ¹H NMR (400 MHz, CDCl₃) 1.67 (br s, 6H), 5.37 (br s,1H), 6.71 (d, J=8.6 Hz, 1H), 7.14 (dd, J=8.6, 2.5 Hz, 1H), 7.33-7.36 (m,1H).

Step 5. Synthesis oftert-butyl{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}carbamate(C49). Cesium carbonate (2.05 g, 6.28 mmol) was added to a solution of4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenol (C48) (500 mg,2.10 mmol) in N,N-dimethylformamide (5 mL).(2S)-2-[(tert-Butoxycarbonyl)amino]propyl methanesulfonate (P12) (0.53g, 2.1 mmol) was added, and the reaction mixture was heated to 60° C.After 30 minutes, additional P12 (0.53 g, 2.1 mmol) was added, andheating was continued for 18 hours. Water (100 mL) was added, and themixture was extracted with diethyl ether (3×50 mL). The combined organiclayers were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. Silica gel chromatography (Gradient: 0% to 15%ethyl acetate in heptane) afforded the product as a colorless oil.Yield: 625 mg, 1.58 mmol, 75%.

Step 6. Synthesis of(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine(C50). Trifluoroacetic acid (5 mL) was added to a solution oftert-butyl{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}carbamate(C49) (600 mg, 1.52 mmol) in dichloromethane (24 mL), and the reactionmixture was stirred for 30 minutes. Aqueous sodium hydroxide solution (1M, 50 mL) was added, and the mixture was extracted with diethyl ether(3×50 mL). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford the product as alight amber oil, which was used without further purification. Yield: 433mg, 1.46 mmol, 96%. LCMS m/z 296.1, 298.1 (M+1). ¹H NMR (400 MHz, CDCl₃)δ 1.24 (d, J=6.4 Hz, 3H), 1.67 (br s, 6H), 2.13 (br s, 2H), 3.41-3.50(m, 1H), 3.79 (dd, half of ABX pattern, J=8.8, 7.2 Hz, 1H), 3.86 (dd,half of ABX pattern, J=8.9, 4.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.23(dd, J=8.8, 2.5 Hz, 1H), 7.36-7.39 (m, 1H).

Step 7. Synthesis ofN-{(2S)-1-K-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C51). Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (97%,398 mg, 1.51 mmol) was added portion-wise over 5 minutes to a solutionof(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine(C50) (400 mg, 1.51 mmol) in tetrahydrofuran (8 mL), and the reactionmixture was heated to 40° C. for 45 minutes.7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione(P14) (555 mg, 2.26 mmol) was then added portion-wise over a period ofapproximately 5 minutes, and the reaction mixture was heated to 70° C.for 6 hours, whereupon it was cooled to 0° C. and slowly quenched withaqueous hydrochloric acid (1 M, 1 mL). After addition of water, themixture was extracted three times with dichloromethane; the combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide the product as a paleyellow solid, which was used in the next step without additionalpurification. Yield: 690 mg, 1.28 mmol, 85%. LCMS m/z 541.3, 543.0(M+1). ¹H NMR (400 MHz, CD₃OD) δ 1.41 (d, J=6.8 Hz, 3H), 1.69 (br s,6H), 2.23 (d, J=1.0 Hz, 3H), 3.85 (t, J=5.8 Hz, 2H), 4.05 (dd, half ofABX pattern, J=9.6, 5.4 Hz, 1H), 4.14 (dd, half of ABX pattern, J=9.6,6.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 2H), 4.48-4.57 (m, 1H), 6.54 (d, J=7.5Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.24-7.26 (m, 1H), 7.31 (dd, J=8.8, 2.6Hz, 1H), 7.37-7.40 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 8.19 (d, J=1.4 Hz,1H).

Step 8. Synthesis of2-{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(117). Diisopropyl azodicarboxylate (94%, 0.314 mL, 1.49 mmol) was addedto a mixture ofN-{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C51) (671 mg, 1.24 mmol) and triphenylphosphine (390 mg, 1.49 mmol) intetrahydrofuran (30 mL), and the reaction mixture was allowed to stir atroom temperature for 1 hour. After removal of solvent in vacuo, theresidue was purified using silica gel chromatography (Gradient: 0% to70% [10% (2 N ammonia in methanol)/90% ethyl acetate] in ethyl acetate),then via chiral HPLC (Column: Phenomenex Cellulose-1, 5 μm; Gradient: 5%to 100% ethanol in heptane), to afford the product as a pale yellowfoam. Yield: 409 mg, 0.782 mmol, 63%. LCMS m/z 523.0, 525.0 (M+1). ¹HNMR (400 MHz, CDCl₃) δ 1.41 (d, J=7.0 Hz, 3H), 1.59-1.62 (m, 6H), 2.35(d, J=1.0 Hz, 3H), 3.59-3.72 (m, 2H), 4.03 (dd, half of ABX pattern,J=10.0, 4.7 Hz, 1H), 4.11 (dd, half of ABX pattern, J=10.0, 8.9 Hz, 1H),4.25 (ddd, J=14.2, 8.1, 4.4 Hz, 1H), 4.46 (ddd, J=14.3, 6.4, 4.3 Hz,1H), 5.16-5.26 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.17-7.19 (m, 1H), 7.25(dd, J=8.8, 2.5 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.36 (br d, J=2.5 Hz,1H), 7.54 (d, J=7.6 Hz, 1H), 8.48 (br s, 1H).

Example 1182-[(2S)-1-{4-Fluoro-2-[(2R)-1,1,1-trifluoropropan-2-yl]phenoxy}propan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(118)

Step 1. Synthesis ofN-{(2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C52). Diisobutylaluminum hydride (1.5 M in toluene, 1.63 mL, 2.44 mmol)was added to a solution of(2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine(P13) (fractions that were enriched in the lower R_(f) diastereomer wereused, see step 4 of Preparation 13; 324 mg, 1.22 mmol) intetrahydrofuran (5 mL). After the vigorous bubbling subsided, thereaction mixture was stirred for 2 hours at room temperature.7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione(P14) (299.7 mg, 1.222 mmol) was added, and the reaction mixture washeated to 60° C. for 24 hours. It was then cooled to room temperature,carefully quenched with 1 M aqueous sodium hydroxide solution, andextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford theproduct as a sticky orange-tan oil. This was used in the following stepwithout additional purification. Yield: 430 mg, 0.84 mmol, 69%. LCMS m/z511.3 (M+1). On large scale, use of diisobutylaluminum hydride was lesssuccessful; in this case, simply dissolving P13 and P14 in methanol,boiling the solution down to a thick homogeneous oil and heating at 110°C. provided superior results.

Step 2. Synthesis of2-[(2S)-1-{4-fluoro-2-[(2R)-1,1,1-trifluoropropan-2-yl]phenoxy}propan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(118). Diisopropyl azodicarboxylate (94%, 0.229 mL, 1.09 mmol) was addedto a solution ofN-{(2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C52) (430 mg, ≦0.84 mmol) and triphenylphosphine (98.5%, 291 mg, 1.09mmol) in tetrahydrofuran (7 mL), and the reaction mixture was stirred atroom temperature for 18 hours. It was then partitioned between water (20mL) and ethyl acetate (30 mL), and the aqueous layer was extracted withethyl acetate. The combined organic layers were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. Purification wascarried out via silica gel chromatography (Eluents: ethyl acetate, then10% methanol in ethyl acetate). Fractions containing the lowest R_(f)spot were combined to afford a tan solid (200 mg), judged by NMR toconsist of a mixture of the product diastereomers. ¹H NMR (400 MHz,CD₃OD), characteristic peaks: δ 1.29-1.42 (m, 6H), 2.22-2.25 (m, 3H),4.01-4.19 (m, 3H), 4.22-4.37 (m, 2H), 5.11-5.25 (m, 1H), 6.99-7.12 (m,3H), 7.25-7.33 (m, 2H), 7.76-7.82 (m, 1H), 8.27-8.32 (m, 1H). Thismaterial was combined with the fractions containing the higher R_(f)product diastereomer, as well as related material derived from startingmaterial enriched in the upper R_(f) diastereomer of P13 (see step 4 ofPreparation 13; 1.10 g, 4.15 mmol) that had in similar fashion beensubjected to the previous step and this Mitsunobu reaction [¹H NMR (400MHz, CDCl₃), characteristic peaks: δ 1.38-1.49 (m, 6H), 2.32-2.35 (m,3H), 6.79-6.85 (m, 1H), 6.95-7.01 (m, 1H), 7.03-7.11 (m, 1H), 7.15-7.19(m, 1H), 7.29-7.34 (m, 1H), [7.52 (d, J=7.6 Hz) and 7.52 (d, J=7.8 Hz),total 1H], 8.40-8.45 (m, 1H)]. Purification of this mixture viasupercritical fluid chromatography (Column: Chiral TechnologiesChiralpak® AD-H, 5 μm; Eluent: 35:65 methanol/carbon dioxide, containing0.2% isopropylamine) provided material (150 mg) that was then slurriedwith diethyl ether (5 mL) and filtered to afford the product. Yield: 98mg, 0.20 mmol, 4% over 2 steps. The stereochemistry of the methyl groupadjacent to the trifluoromethyl moiety was established by single crystalX-ray crystallography on a sample prepared in a related manner. LCMS m/z493.3 (M+1). ¹H NMR (400 MHz, CD₃OD) δ 1.36-1.40 (m, 6H), 2.24 (d, J=1.2Hz, 3H), 3.64 (ddd, J=13.6, 8.1, 4.2 Hz, 1H), 3.80 (ddd, J=13.6, 6.9,4.1 Hz, 1H), 4.01-4.17 (m, 3H), 4.22-4.37 (m, 2H), 5.15-5.25 (m, 1H),7.02-7.05 (m, 2H), 7.06-7.11 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.31-7.33(m, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.31 (d, J=1.2 Hz, 1H).

Example 1192-{(2S)-1-[4-Chloro-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(119)

Step 1. Synthesis of1-(2-hydroxyethyl)-N-[(2S)-1-hydroxypropan-2-yl]-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C53). A mixture of7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione(P14) (1.440 g, 5.872 mmol) and (2S)-2-aminopropan-1-ol (1.714 g, 22.82mmol) in acetonitrile (3 mL) was heated to 85° C. for 20 minutes. Thereaction mixture was then allowed to cool to room temperature anddiluted with additional acetonitrile (10 mL). Filtration and rinsingwith acetonitrile (10 mL) afforded the product as a white solid. Yield:1.62 g, 5.06 mmol, 86%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.11 (d, J=6.8 Hz,3H), 2.14 (d, J=0.9 Hz, 3H), 3.33-3.46 (m, 2H), 3.59-3.66 (m, 2H),3.89-4.01 (m, 1H), 4.18-4.29 (m, 2H), 4.80 (t, J=5.8 Hz, 1H), 4.94 (t,J=5.4 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 7.32-7.34 (m, 1H), 7.69 (d, J=7.5Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 8.67 (br d, J=8.3 Hz, 1H).

Step 2. Synthesis of2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C54). Diisopropyl azodicarboxylate (95%, 2.58 mL, 12.7 mmol) was addeddrop-wise to a solution of1-(2-hydroxyethyl)-N-[(2S)-1-hydroxypropan-2-yl]-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide(C53) (1.622 mg, 5.063 mmol) and triphenylphosphine (3.35 g, 12.7 mmol)in tetrahydrofuran (20 mL), and the reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated ontosilica gel and purified by silica gel chromatography (Eluents: ethylacetate, followed by 5%, then 10%, then 25% methanol in ethyl acetate).Fractions containing the product were combined and concentrated in vacuoto near-dryness, then layered with ethyl acetate and allowed to stand.The resulting precipitate was collected by filtration to provide theproduct as a white solid. Yield: 446 mg, 1.48 mmol, 29%. ¹H NMR (400MHz, DMSO-d₆) δ 1.10 (d, J=6.9 Hz, 3H), 2.15 (d, J=1.0 Hz, 3H),3.41-3.53 (m, 2H), 3.59-3.65 (m, 2H), 4.14-4.28 (m, 2H), 4.53-4.62 (m,1H), 4.83 (t, J=5.7 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.40-7.42 (m, 1H),7.79 (d, J=7.8 Hz, 1H), 8.25 (d, J=1.4 Hz, 1H).

Step 3. Synthesis of7-(4-methyl-1H-imidazol-1-yl)-2-{(2S)-1-[4-nitro-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C55). A solution of potassium tert-butoxide in tetrahydrofuran (1 M,1.97 mL, 1.97 mmol) was added to a slurry of2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C54) (541 mg, 1.79 mmol) in tetrahydrofuran (6 mL), and the mixture wasallowed to stir for 10 minutes. A solution of1-fluoro-4-nitro-2-(pentafluoro-λ⁶-sulfanyl)benzene (P15) (478 mg, 1.79mmol) in tetrahydrofuran (4 mL) was added, and the reaction mixture wasstirred at room temperature for 18 hours. At that point, it was dilutedwith water and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated invacuo. Purification via silica gel chromatography (Eluents: ethylacetate, then 10% methanol in ethyl acetate) afforded the product as ayellow foam. Yield: 695 mg, 1.26 mmol, 70%. LCMS m/z 550.2 (M+1). ¹H NMR(400 MHz, CDCl₃) δ 1.53 (d, J=7.1 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H),3.73-3.85 (m, 2H), 4.30-4.47 (m, 4H), 4.99-5.08 (m, 1H), 7.16-7.21 (m,2H), 7.28 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 8.40 (dd, J=9.2,2.7 Hz, 1H), 8.44 (br s, 1H), 8.71 (d, J=2.6 Hz, 1H).

Step 4. Synthesis of2-{(2S)-1-[4-amino-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C56). A mixture of7-(4-methyl-1H-imidazol-1-yl)-2-{(2S)-1-[4-nitro-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C55) (790 mg, 1.44 mmol) and ethanol (10 mL) was heated to 55° C. Ironpowder (99%, 243 mg, 4.31 mmol) and a solution of ammonium chloride (462mg, 8.64 mmol) in water (2.5 mL) were added, and the reaction mixturewas stirred at reflux for 3 hours. The reaction mixture was allowed tocool to room temperature, concentrated in vacuo, treated with ethylacetate and saturated aqueous sodium bicarbonate solution and filteredthrough Celite. The filter pad was rinsed with water and ethyl acetate;the organic portion of the filtrate was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. Purification via silica gelchromatography (Gradient: 5% to 10% methanol in ethyl acetate) providedthe product as a light yellow foam. Yield: 507 mg, 0.98 mmol, 68%. LCMSm/z 520.2 (M+1). ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 1.48(d, J=7.2 Hz, 3H), 3.71-3.79 (m, 1H) 3.85-3.92 (m, 1H), 4.05 (dd, J=9.6,5.5 Hz, 1H), 4.99-5.08 (m, 1H), 6.80 (dd, half of ABX pattern, J=8.8,2.6 Hz, 1H), 6.86 (br d, half of AB quartet, J=8.8 Hz, 1H), 7.06 (d,J=2.6 Hz, 1H).

Step 5. Synthesis of2-{(2S)-1-[4-chloro-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(119). A solution of2-{(2S)-1-[4-amino-2-(pentafluoro-λ⁶-sulfanyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(C56) (507 mg, 0.976 mmol) in a mixture of acetone (40 mL) andconcentrated hydrochloric acid (4 mL) was cooled to −8° C. A solution ofsodium nitrite (67.3 mg, 0.975 mmol) in water (5 mL) was added, thecooling bath was removed, and the reaction mixture was stirred at roomtemperature for 1 hour. The resulting orange solution was cooled to −2°C., and copper(I) chloride (99 mg, 1.0 mmol) was added. After two hoursat room temperature, the reaction mixture was diluted with water (100mL), and concentrated ammonium hydroxide was added drop-wise until thepH reached approximately 8. The bright blue mixture was extracted withethyl acetate (2×75 mL), and the combined organic layers were washedwith a 1:1 mixture of concentrated ammonium hydroxide and water(approximately 30 mL) until the aqueous layer was essentially colorless.The organic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. Purification was first carried out by HPLC (Column:Phenomenex Luna C18, 5 μm; Mobile phase A: 0.1% formic acid in water;Mobile phase B: 0.1% formic acid in methanol; Gradient: 5% to 95% B) toafford 315 mg of the product, presumed to be a formate salt, as a lightorange gum. This material was dissolved in ethyl acetate, washed withsaturated aqueous sodium bicarbonate solution, washed with saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated in vacuo to afford a solid. This was furtherpurified via silica gel chromatography (Eluents: 5%, then 10% methanolin ethyl acetate); the desired material was reconcentrated from diethylether to afford the product as a white solid. Yield: 217 mg, 0.403 mmol,41%. LCMS m/z 539.2 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 1.50 (d, J=7.2 Hz,3H), 2.33 (d, J=1.0 Hz, 3H), 3.75 (ddd, half of ABXY pattern, J=13.5,7.6, 4.2 Hz, 1H), 3.83 (ddd, half of ABXY pattern, J=13.5, 7.2, 4.2 Hz,1H), 4.16 (dd, J=9.6, 5.6 Hz, 1H), 4.26-4.34 (m, 2H), 4.39 (ddd, half ofABXY pattern, J=14.3, 7.2, 4.2 Hz, 1H), 4.99-5.08 (m, 1H), 6.99 (d,J=9.0 Hz, 1H), 7.16-7.18 (m, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.46 (dd,J=8.9, 2.5 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H),8.40-8.42 (m, 1H).

METHODS Method A Preparation of 2-[2-(aryloxy)ethyl] and2-[2-(heteroaryloxy)ethyl]7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones

2-(2-Chloroethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P2) (10-20 mg) and a hydroxyaryl or hydroxyheteroaryl reactant (1-4equivalents) were combined in dimethyl sulfoxide (P2 concentration0.06-0.08 M). After addition of potassium carbonate (3.5 equivalents),the reaction mixture was heated at 100° C. until the reaction was judgedto be complete via LCMS analysis (generally 1-3 hours). The mixture wasthen cooled to room temperature and filtered; the filtrate wasconcentrated in vacuo and purified using either silica gelchromatography or by reversed-phase HPLC with an appropriate gradientusing one of the following systems:

a) Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05%trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v);

b) Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammoniumhydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide inacetonitrile (v/v);

c) Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% formicacid in water (v/v); Mobile phase B: 0.05% formic acid in acetonitrile(v/v).

Method B Preparation of ortho-substituted7-(4-methyl-1H-imidazol-1-yl)-2-(2-phenoxyethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionesvia Suzuki coupling

The boronic acid (72 μmol) was weighed into a vial and a solution of2-[2-(2-bromophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione(P8) (26.5 mg, 0.060 mmol) in 1,4-dioxane (750 μL) was added. Next, asolution of cesium carbonate (43.2 mg, 0.12 mmol) in water (150 μL) wasadded and nitrogen was bubbled through the reaction. Dichloro[1,1′bis(di-tert-butylphosphino)]ferrocene palladium(II) (2 mg, 0.003 mmol)was then added, nitrogen was bubbled through the reaction and the vialwas capped and heated to 100° C. for 16 hours. The reaction wasfiltered; the solvent was removed in vacuo and the residue was purifiedby preparative reversed-phase HPLC. Purifications were carried out usingan appropriate gradient on either a DIKMA Diamonsil(2) C18 column (5 μm)or a Boston Symmetrix C18 ODS-H column (5 μm), with the aqueous and theacetonitrile mobile phases each containing 0.225% formic acid.

TABLE 1

Ex #*

Method of Preparation; Non- commercial Starting Materials IUPAC Name ¹HNMR (400 MHz, CDCl₃), δ (ppm); Mass spectrum, observed ion m/z (M + 1)or HPLC retention time (minutes); Mass spectrum m/z (M + 1) (unlessotherwise indicated) 3

Preparation 3, Ex 1 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(1-naphthyloxy)ethyl]-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.28(d, J = 1.0 Hz, 3H), 4.01-4.05 (m, 2H), 4.14 (dd, J = 5.1, 4.5 Hz, 2H),4.37-4.41 (m, 2H), 4.46 (dd, J = 5.0, 4.6 Hz, 2H), 6.82 (dd, J = 7.6,0.7 Hz, 1H), 7.11-7.12 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.37 (dd, J =8.2, 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.45-7.54 (m, 3H), 7.80-7.85(m, 1H), 8.11- 8.16 (m, 1H), 8.21 (d, J = 1.3 Hz, 1H); 415.1 4

Ex 1¹ 2-[2-(2,3-dichlorophenoxy)- 2-methylpropyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 1.42(s, 6H), 2.29 (s, 3H), 3.90 (s, 2H), 4.08-4.13 (m, 2H), 4.37-4.42 (m,2H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 7.11-7.16 (m, 2H), 7.23 (dd, J =8.0, 1.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H),8.23 (s, 1H); 461.2 5

Ex 1² 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[4-(trifluoromethyl)phenoxy]pro pyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.51 min⁴⁹; 447.2 6

Method A 2-{2-[(4-chloro-2- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.62 min⁴⁹; 449.2, 451.2 7

Method A 2-{2-[(7-methoxy-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.42 min⁴⁹; 445.2 8

Method A 2-{2-[(4-methoxy-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.19 min⁴⁹; 445.2 9

Method A³ 2-{2-[(7-chloro-2,3-dihydro- 1H-inden-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.34 min⁴⁹; 439.2, 441.2 10

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(2,3,5-trichlorophenoxy)ethyl]-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione2.42 min⁴⁹; 466.9 11

Method A⁴ 2-{2-[(7-fluoro-1-benzofuran- 4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.12min⁴⁹; 423.0 12

Method A 2-{2-[4-chloro-3- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.41 min⁴⁹; 466.9, 468.9 13

Method A 2-[2-(2-tert- butylphenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.33 min⁴⁹; 421.3 14

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(5,6,7,8-tetrahydronaphthalen-1- yloxy)ethyl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.38 min⁴⁹; 419.0 15

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(trifluoromethoxy)phenoxy]eth- yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.37 min⁴⁹; 449.2 16

Method A 2-[2-(2,3-dihydro-1H-inden- 4-yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.16min⁴⁹; 405.2 17

Method A 2-[2-(2-chloro-4- methylphenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.18 min⁴⁹; 413.0, 415.0 18

Method A 2-[2-(biphenyl-3-yloxy)ethyl]- 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H- pyrido[1,2-a]pyrazine-1,6- dione 2.38 min⁴⁹; 441.019

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(3-phenoxyphenoxy)ethyl]-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione2.62 min⁴⁹; 457.3 20

Method A 2-[2-[2-chloro-3- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.47 min⁴⁹; 467.2, 469.1 21

Method A⁵ 2-[2-(2-cyclopropyl-4- fluorophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.43 min⁴⁹; 423.2 22

Preparation 8⁶ 2-{2-[4-chloro-2- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione ¹H NMR (400 MHz, CD₃OD) δ 2.24 (d, J =0.9 Hz, 3H), 3.90-3.94 (m, 2H), 4.01 (dd, J = 5.1, 5.0 Hz, 2H),4.32-4.39 (m, 4H), 7.21-7.27 (m, 2H), 7.30-7.32 (m, 1H), 7.56- 7.60 (m,2H), 7.76 (d, J = 7.7 Hz, 1H), 8.30 (d, J = 1.3 Hz, 1H); 467.1 23

Method A⁷ 2-[2-(2,3-dichloro-4- fluorophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.44 min⁴⁹; 451.1, 453.1 24

Method A⁸ 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(3- methylisothiazol-5-yl)phenoxy]ethyl}-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.04min⁴⁹; 462.0 25

Method A⁹ 2-[2-(2- cyclobutylphenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.36 min⁴⁹; 419.0 26

Method A¹⁰ 2-[2-(dibenzo[b,d]furan-4- yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.35min⁴⁹; 454.9 27

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(2,3,4-trichlorophenoxy)ethyl]-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione¹H NMR (500 MHz, CDCl₃) δ 2.29 (s, 3H), 4.01-4.06 (m, 4H), 4.30 (dd, J =4.9, 4.6 Hz, 2H), 4.40-4.44 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 7.13-7.14(m, 1H), 7.24-7.26 (m, 1H, assumed; partirally obscured by solventpeak), 7.35 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 8.23 (br s,1H); 467 28

Ex 1 2-[3-(4-chloro-3,5- dimethylphenoxy)propyl]-7-(4-methyl-1H-imidazol-1-yl)- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.68 min⁴⁹; 441.2, 443.2 29

Method A¹¹ 2-{2-[2,4- bis(trifluoromethyl)phenoxy]eth-yl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.62 min⁴⁹; 501.2 30

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-[2-(2,4,5-trichlorophenoxy)ethyl]-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione2.62 min⁴⁹; 467.1, 469.1, 471.1 31

Method A 2-(2-{[2,6- bis(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.46 min⁴⁹; 502.3 32

Ex 1 2-[3-(2-tert- butylphenoxy)propyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.76 min⁴⁹; 435.2 33

Ex 1 2-[2-(2,3- dichlorophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.11 min⁴⁹; 433.1, 435.1 34

Ex 1 2-[2-(biphenyl-2-yloxy)ethyl]- 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H- pyrido[1,2-a]pyrazine-1,6- dione, trifluoroacetatesalt 0.85 min⁵⁰; 441.5 35

Method A¹² 2-{2-[2-chloro-4-fluoro-3- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione, trifluoroacetate salt 2.53 min⁴⁹;485.2, 487.2 36

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(2-methyl-1,3-thiazol-4-yl)phenoxy]ethyl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.33 min⁵¹; 462.2 37

Method A¹³ 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(4-methylisothiazol-5- yl)phenoxy]ethyl}-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.28 min⁴⁹; 462.2 38

Method A¹⁴ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{4-methyl-2-[5-(trifluoromethyl)isoxazol-3- yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 2.61min⁴⁹; 514.3 39

Method A¹⁴ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{2-[5-(trifluoromethyl)isoxazol-3- yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 2.45min⁴⁹; 500.3 40

Ex 1; P3 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{2-[2-(trifluoromethyl)-1,3-thiazol- 4-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.28 (br s, 3H), 3.69-3.73(m, 2H), 4.09 (dd, J = 5, 5 Hz, 2H), 4.20-4.24 (m, 2H), 4.38 (dd, J = 5,5 Hz, 2H), 7.02 (d, J = 8.6 Hz, 1H), 7.09-7.14 (m, 2H), 7.24-7.27 (m,1H, assumed; partially obscured by solvent peak), 7.35-7.40 (m, 1H),7.44 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 8.05 (dd, J = 7.7, 1.7 Hz, 1H),8.21 (d, J = 1.4 Hz, 1H); 516.2 41

Method A¹⁵ 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(2-methyl-1,3-oxazol-4-yl)phenoxy]ethyl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.21 min⁵¹; 446.3 42

Method A 2-[2-(dibenzo[b,d]furan-1- ylxoy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione,trifluoroacetate salt 2.57 min⁴⁹; 455.3 43

Method A¹⁶ 2-[2-(4-chloro-2-isoxazol-3- ylphenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.39 min⁴⁹; 466.2, 468.2 44

Method A¹⁷ 2-{2-[4-chloro-2-(1-hydroxy- 1-methyl-ethyl)phenoxy]ethyl}-7-(4- methyl-1H-imdiazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 2.19min⁴⁹; 457.3, 459.3 45

Method A¹⁸ 2-{2-[4-chloro-3-fluoro-2- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione, trifluoroacetate salt 2.59 min⁴⁹;485.2, 487.3 46

Method A 2-{2-[(5,8-dichloro-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.73 min⁴⁹; 483.2, 485.2 47

Method A 2-(2-{[6-chloro-7- (trifluoromethyl)quinolin-2-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.04 min⁴⁹; 518.3 48

Method A¹⁹ 2-(2-{4-fluoro-2-[2- (trifluoromethyl)pyridin-4-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.30 min⁴⁹; 528.2 49

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{2-[5-(trifluoromethyl)-1H-pyrazol- 3-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.45 min⁴⁹; 499.1 50

Method A²⁰ 2-(2-{4-chloro-2-[3- (trifluoromethyl)-1H-pyrazol-1-yl]phenoxy)ethyl}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 3.63min⁴⁹; 533.0, 535.0 51

Method A 2-(2-{[5-chloro-8-methyl-2- (trifluoromethyl)quinolin-4-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.87 min⁴⁹; 532.3, 534.3 52

Ex 1, Preparation 3 2-(2-{4-fluoro-2-[2- (trifluoromethyl)-1,3-thiazol-4-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.29 (br s, 3H), 3.71-3.75(m, 2H), 4.11 (dd, J = 5, 5 Hz, 2H), 4.26-4.30 (m, 2H), 4.34 (dd, J = 5,5 Hz, 2H), 6.96 (dd, J = 9.3, 4.3 Hz, 1H), 7.03-7.09 (m, 1H), 7.12 (brs, 1H), 7.25- 7.27 (m, 1H, assumed; partially obscured by solvent peak),7.44 (d, J = 7.5 Hz, 1H), 7.88 (dd, J = 9.3, 3.1 Hz, 1H), 8.17 (s, 1H),8.22 (d, J = 1 Hz, 1H); 534.2 53

Method A 2-{2-[(6-fluoro-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.47 min⁴⁹; 433.3 54

Method A²¹ 2-(2-{5-methoxy-2-[5- (trifluoromethyl)-1H-pyrazol-3-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.47 min⁴⁹; 529.1 55

Ex 1²² 2-{2-[4-fluoro-2- (trifluoromethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione, formate salt ¹H NMR (400 MHz,CD₃OD) δ 1.41 (d, J = 7.0 Hz, 3H), 2.28 (br s, 3H), 3.73-3.85 (m, 2H),4.19- 4.38 (m, 4H), 5.01-5.11 (m, 1H), 7.20-7.25 (m, 1H), 7.25 (d, J =7.7 Hz, 1H), 7.30-7.37 (m, 2H), 7.42 (br s, 1H), 7.83 (d, J = 7.8 Hz,1H), 8.14 (s, 1H), 8.61 (br s, 1H); 465.0 56

Method A²³ 2-(2-{[1-(4-fluoro-2- methylphenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.49min⁴⁹; 531.3 57

Ex 1; P4 2-{(1S)-2-[4-fluoro-2- (trifluoromethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione ¹H NMR (400 MHz, CD₃OD) δ 1.42 (d, J= 7.0 Hz, 3H), 2.24 (d, J = 1.0 Hz, 3H), 3.73-3.85 (m, 2H), 4.20-4.38(m, 4H), 5.02- 5.12 (m, 1H), 7.21-7.26 (m, 1H), 7.26 (d, J = 7.8 Hz,1H), 7.31-7.37 (m ,3H), 7.78 (d, J = 7.7 Hz, 1H), 8.30 (d, J = 1.4 Hz,1H); 465.2 58

Method A 2-(2-{2-[3- (difluoromethyl)isoxazol-5- yl]phenoxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.39 min⁴⁹; 482.3 59

Method A²¹ 2-(2-{4-chloro-2-[5- (trifluoromethyl)-1H-pyrazol-3-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.64 min⁴⁹; 533.0, 535.0 60

Method A 2-{2-[(5-methoxy-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.47 min⁴⁹; 445.3 61

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{[7-(trifluoromethyl)quinolin-4- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.24 min⁵¹; 484.1 62

Method A²⁴ 2-(2-{[6-chloro-8-methyl-2- (trifluoromethyl)quinolin-4-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.91 min⁴⁹; 532.3, 534.3 63

Method A 2-(2-{[8-chloro-2- (trifluoromethyl)quinolin-4-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.63 min⁴⁹; 518.3, 520.3 64

Method A²⁵ 2-{2-[(5-fluoro-6-methoxy-1- naphthyl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, trifluoroacetate salt 2.48 min⁴⁹; 463.3 65

Method A²⁶ 2′-{2-[7-(4-methyl-1H- imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H- pyrido[1,2-a]pyrazin-2- yl]ethoxy}-3-(trifluoromethyl)biphenyl-4- carbonitrile 2.66 min⁴⁹; 534.1 66

Method A²⁴ 2-(2-{[8-chloro-5-fluoro-2- (trifluoromethyl)quinolin-4-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.65 min⁴⁹; 536.3, 538.3 67

Method A²⁷ 2-{2-[3-chloro-4-fluoro-2- (trifluoromethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.27 min⁴⁹; 484.9, 486.9 68

Ex 1²⁸ 2-{2-[(4-chloroisoquinolin-1- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione,trifluoroacetate salt 2.48 min⁴⁹; 450.3, 452.3 69

Method A 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{[6-(trifluoromethyl)quinolin-4- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.14 min⁵¹; 484.0 70

Ex 1²⁹ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{3-[4-(pent-4-yn-1-yloxy)benzoyl]phenoxy}ethyl)- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 1.99-2.09 (m, 3H), 2.29 (s, 3H), 2.42-2.48 (m, 2H),3.91-3.96 (m, 2H), 3.98- 4.03 (m, 2H), 4.15-4.20 (m, 2H), 4.30-4.34 (m,2H), 4.36-4.42 (m, 2H), 6.95-7.00 (m, 2H), 7.07- 7.12 (m, 1H), 7.14 (brs, 1H), 7.26-7.47 (m, 5H, assumed; partially obscured by solvent peak),7.79-7.83 (m, 2H), 8.23 (br s, 1H); 551.3 71

Method A³⁰ 2-{2-[(9-methyl-9H-carbazol- 4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione,trifluoroacetate salt 2.11 min⁴⁹; 468.1 72

Method A; P5 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{2-[3-(trifluoromethyl)isoxazol-5- yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.29 (d, J = 1.0 Hz, 3H),3.79-3.84 (m, 2H), 4.12 (dd, J = 5.3, 4.9 Hz, 2H), 4.31-4.35 (m, 2H),4.41 (dd, J = 5.3, 4.9 Hz, 2H), 7.00 (s, 1H), 7.06 (br d, J = 8.6 Hz,1H), 7.12-7.17 (m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz,1H), 7.49 (ddd, J = 8.5, 7.4, 1.7 Hz, 1H), 7.91 (dd, J = 7.8, 1.8 Hz,1H), 8.30 (d, J = 1.2 Hz, 1H); 500.2 73

Method A; P6 2-(2-{[4-fluoro-2- (trifluoromethyl)-1,3-benzothiazol-7-yl]oxy}ethyl)- 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H- pyrido[1,2-a]pyrazine-1,6- dione 2.29 (d, J = 0.8Hz, 3H), 3.94-3.99 (m, 2H), 4.07 (dd, J = 5.0, 4.8 Hz, 2H), 4.41-4.48(m, 4H), 6.92 (dd, J = 8.7, 3.1 Hz, 1H), 7.12-7.14 (m, 1H), 7.23- 7.29(m, 2H), 7.45 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H); 508.2 74

Ex 1³¹ 2-[2-([1]benzofuro[3,2- c]pyridin-1-yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.28 (d, J = 0.9 Hz, 3H), 3.85-3.89 (m, 2H), 4.15-4.19 (m, 2H), 4.31-4.35 (m, 2H), 4.89-4.92 (m, 2H), 7.11-7.13 (m, 1H),7.22 (d, J = 5.9 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.41 (ddd, J = 7.5,7.5, 1.1 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.50 (ddd, J = 8.2, 7.4, 1.4Hz, 1H), 7.61 (ddd, J = 8.2, 0.9, 0.8 Hz, 1H), 8.01 (ddd, J = 7.7, 1.40.6 Hz, 1H), 8.15 (d, J = 6.9 Hz, 1H), 8.21 (br d, J = 1.3 Hz, 1H);456.3 75

Ex 1³² 2-[2-({5-fluoro-3-[2- (trifluoromethyl)-1,3-thiazol-4-yl]pyridin-2-yl}oxy)ethyl]-7- (4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.28 (d, J = 0.8 Hz,3H), 3.72-3.77 (m, 2H), 4.14- 4.18 (m, 2H), 4.30-4.35 (m, 2H), 4.71-4.75(m, 2H), 7.11-7.12 (m, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.8Hz, 1H), 7.99 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.38 (dd, J= 8.7, 3.0 Hz, 1H), 8.42 (s, 1H); 535.1 76

Method A; P7 2-{2-[2-(3,3- difluorocyclobutyl)-4-fluorophenoxy]ethyl}-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.52 min⁴⁹; 473.1 77

Method A 2-{2-[(5-chloro-1,2- benzisothiazol-3-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.30 (d, J = 1.0 Hz, 3H), 3.85-3.89(m, 2H), 4.08- 4.11 (m, 2H), 4.35-4.39 (m, 2H), 4.82-4.86 (m, 2H),7.13-7.15 (m, 1H), 7.28 (d, 1H, assumed; partially obscured by solventpeak), 7.46 (d, J = 7.7 Hz, 1H), 7.51 (dd, J = 8.6, 1.9 Hz, 1H), 7.72(dd, J = 8.6, 0.5 Hz, 1H), 7.80 (dd, J = 2.0, 0.6 Hz, 1H), 8.28 (br d, J= 1.0 Hz, 1H); 456.2 78

Method A 2-{2-[(6-methoxy-1- naphthyl)oxy]ethyll}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.37 min⁴⁹; 445.3 79

Method A³³ 2-[2-(dibenzo[b,d]thien-1- yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.51min⁴⁹; 471.0 80

Method A³⁴ 2-(2-{[7-fluoro-2- (trifluoromethyl)-1,3-benzothiazol-4-yl]oxy}ethyl)- 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H- pyrido[1,2-a]pyrazine-1,6- dione 2.50 min⁴⁹; 508.081

Method A³⁵ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{3-[3-(trifluoromethyl)-1H-pyrazol- 1-yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 2.44min⁴⁹; 499.0 82

Method A 2-{2-[(5-chloro-1,2- benzisoxazol-3-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.30 (d, J = 0.8 Hz, 3H), 3.86-3.90 (m,2H), 4.10 (dd, J = 5.1, 5.1 Hz, 2H), 4.38-4.42 (m, 2H), 4.75 (dd, J =5.3, 5.1 Hz, 2H), 7.14 (br s, 1H), 7.28 (d, J = 8 Hz, 1H, assumed;partially obscured by solvent peak), 7.40 (br d, J = 8.8 Hz, 1H), 7.46(d, J = 7.8 Hz, 1H), 7.52 (dd, J = 8.9, 2.0 Hz, 1H), 7.57 (br d, J = 2Hz, 1H), 8.27 (br d, J = 1 Hz, 1H); 440.2, 442.2 83

Method A; Example 2 for phenol 2-{2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.27 (d, J = 1.0 Hz, 3H), 3.96-4.01(m, 2H), 4.13 (dd, J = 5.1, 4.6 Hz, 2H), 4.36-4.41 (m, 2H), 4.43 (dd, J= 5.1, 4.7 Hz, 2H), 6.84 (br d, J = 7.7 Hz, 1H), 7.10-7.12 (m, 1H),7.25- 7.30 (m ,1H), 7.28 (d, J = 7.7 Hz, 1H), 7.33 (dd, J = 8.1, 7.8 Hz,1H), 7.42 (d, J = 7.7 Hz, 1H), 7.45 (br d, J = 8.3 Hz, 1H), 7.70 (br dd,J = 10.4, 2.7 Hz, 1H), 7.80 (dd, J = 9.0, 5.6 Hz, 1H), 8.21 (d, J = 1.3Hz, 1H); 433 84

Method A 2-(2-{[7-chloro-2- (trifluoromethyl)quinolin-4-yl]oxy}ethyl)-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.31 (s, 3H), 3.97-4.02 (m, 2H),4.19 (dd, J = 5.1, 4.9 Hz, 2H), 4.40-4.45 (m, 2H), 4.57 (dd, J = 5.1,4.9 Hz, 2H), 7.07 (s, 1H), 7.16 (br s, 1H), 7.32 (d, J = 7.8 Hz, 1H),7.56 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 9.0, 2.1 Hz, 1H), 8.07 (d, J =8.8 Hz, 1H), 8.15 (d, (d, J = 2.0 Hz, 1H), 8.55 (br s, 1H); 518.2 85

Method A³⁵ 2-(2-{4-fluoro-2-[3- (trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.13 min⁴⁹; 517.0 86

Method A³⁶ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{[1-(trifluoromethyl)isoquinolin-4- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione, trifluoroacetate salt 2.41 min⁴⁹;484.3 87

Method A³⁷ 2-{2-[(4- fluorodibenzo[b,d]furan-1-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.28 (d, J = 0.8 Hz, 3H), 3.94-3.99(m, 2H), 4.17 (dd, J = 5.1, 4.9 Hz, 2H), 4.35-4.39 (m, 2H), 4.49 (dd, J= 5.1, 4.9 Hz, 2H), 6.68 (dd, J = 8.8, 2.7 Hz, 1H), 7.10-7.17 (m, 2H),7.31 (d, J = 7.8 Hz, 1H), 7.38 (ddd, J = 7.6, 7.4, 0.8 Hz, 1H), 7.44 (d,J = 7.8 Hz, 1H), 7.50 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.63 (br d, J =8.4 Hz, 1H), 8.05 (ddd, J = 7.8, 1.4, 0.6 Hz, 1H), 8.21 (d, J = 1.4 Hz,1H); 473 88

Method B 2-{2-[(3′-fluorobiphenyl-2- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione, formatesalt 2.78 min⁵²; 459 89

Method B 2-{2-[(4′-fluorobiphenyl-2- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione, formatesalt 2.76 min⁵²; 459 90

Method B 2′-{2-[7-(4-methyl-1H- imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H- pyrido[1,2-a]pyrazin-2- yl]ethoxy}biphenyl-4-carbonitrile, formate salt 2.65 min⁵²; 466 91

Method B 2-{2-[2-(1,3-benzodioxol-5- yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 2.74 min⁵²; 485 92

Method B 2-{2-[2-(1-benzofuran-2- yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, formate salt 2.92 min⁵²; 481 93

Method B 2-{2-[(4′-methylbiphenyl-2- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione, formatesalt 2.86 min⁵²; 455 94

Method B 2-{2-[(4′-chlorobiphenyl-2- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione, formatesalt 2.85 min⁵²; 475 95

Method B 2-{2-[(3′-methylbiphenyl-2- yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro- 2H-pyrido[1,2-a]pyrazine- 1,6-dione, formatesalt 2.86 min⁵²; 455 96

Method A³⁸ 2-{2-[(6,7- difluoronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione, trifluoroacetate salt 2.53 min⁴⁹;451.2 97

Method A; P9 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{[2-(trifluoromethyl)-1,3-benzothiazol-7- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione, trifluoroacetate salt 2.31 min⁴⁹;490.0 98

Method A³⁹ 2-{2-[(4,7- difluoronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.28 (br s, 3H), 3.96-4.02 (m, 2H),4.12 (dd, J = 4.9, 4.9 Hz, 2H), 4.37-4.44 (m, 4H), 6.73 (dd, J = 8.3,3.8 Hz, 1H), 6.99 (dd, J = 10.0, 8.4 Hz, 1H), 7.12 (br s, 1H), 7.30 (d,J = 7.6 Hz, 1H), 7.35 (ddd, J = 8.8, 8.6, 2.5 Hz, 1H), 7.44 (d, J = 7.6Hz, 1H), 7.67-7.72 (m, 1H), 8.06 (dd, J = 9.2, 5.5 Hz, 1H), 8.22 (br s,1H); 451.5 99

Ex 1²⁸ 2-{2-[(4-chloro-7- fluoroisoquinolin-1-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione, trifluoroacetate salt 2.51 min⁴⁹;468.2, 470.2 100

Ex 1⁴⁰ 2-{1-[4-chloro-2-(tri- fluoromethyl)phenoxy]butan-2-yl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione, trifluoroacetate salt 2.70 min⁴⁹;495.3, 497.3 101

Preparation 3⁴¹, Ex 1 7-(4-methyl-1H- imidazol-1-yl)-2-(2-{[2-(trifluoromethyl)-1H-indol-4- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.34 min⁴⁹; 472.2 102

Method A⁴² 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{[1-methyl-2-(trifluoromethyl)-1H-indol-4- yl]oxy}ethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.60 min⁴⁹; 486.2 103

Ex 1⁴⁰ 2-{1-[4-fluoro-2-(trifluoro- methyl)phenoxy]butan-2-yl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 1.04 (t, J = 7.3 Hz, 3H), 1.82-2.02(m, 2H), 2.35 (s, 3H), 3.71-3.79 (m ,1H), 3.83-3.91 (m, 1H), 4.18- 4.28(m, 2H), 4.29-4.38 (m, 2H), 4.75-4.83 (m, 1H), 6.95 (dd, J = 9.1, 4.0Hz, 1H), 7.19-7.26 (m, 2H), 7.29-7.34 (m, 2H), 7.62 (d, J = 7.8 Hz, 1H),8.54 (br s, 1H); 479.2 104

Method A⁴³ 7-(4-methyl-1H-imidazol-1- yl)-2-(2-{2-[3-(trifluoromethyl)-1,2,4- thiadiazol-5- yl]phenoxy}ethyl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione 2.36 (s, 3H), 3.86-3.91 (m,2H), 4.19 (dd, J = 5.5, 5.5 Hz, 2H), 4.33-4.38 (m, 2H), 4.67 (dd, J =5.5, 5.4 Hz, 2H), 7.15-7.20 (m, 2H), 7.24 (br ddd, J = 8.7, 1 Hz, 1H),7.29 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.59 (ddd, J = 8.4,7.4, 1.7 Hz, 1H), 8.48-8.53 (m, 2H); 517.2 105

Method A⁴⁴ 2-{2-[4-fluoro-2-(1,1,1- trifluoro-2-methylpropan-2-yl)phenoxy]ethyl}-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione characeteristic peaks: 1.67(br s, 6H), 2.57 (d, J = 1.1 Hz, 3H), 4.01-4.06 (m, 2H), 4.24-4.28 (dd,J = 5, 5 Hz, 2H), 6.87-6.91 (m, 1H), 7.15 (dd, J = 11, 3 Hz, 1H),7.30-7.32 (m, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H);493.1 106

Method A⁴⁵ 2-{2-[2-(bicyclo[1.1.1]pent-1- yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4- dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.14 (s, 6H), 2.32 (s, 3H), 2.56 (s, 1H), 3.86-3.91(m, 2H), 4.03 (dd, J = 5.2, 5.0 Hz, 2H), 4.28 (dd, J = 5.2, 4.9 Hz, 2H),4.34-4.39 (m, 2H), 6.82 (dd, J = 8.2, 0.7 Hz, 1H), 6.92 (ddd, J = 7.4,7.4, 1.0 Hz, 1H), 7.09 (dd, J = 7.4, 1.8 Hz, 1H), 7.15- 7.20 (m, 2H),7.30 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 8.37 (br s, 1H);431.1 107

Ex 1⁴⁶ 2-[(2S)-1-[4-chloro-2-(tri- fluoromethyl)phenoxy]propan-2-yl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.46 min⁴⁹; 481.0 108

Method A⁴⁷ 2-{2-[(2,2-difluoro-2,3- dihydro-1H-inden-4-yl)oxy]ethyl}-7-(4-methyl-1H- imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 2.00 min⁴⁹; 441.0 109

Method A⁴⁸ 2-{2-[(2,2-difluoro-1,3- benzodioxol-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1- yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 2.49 (s, 3H), 3.95-4.03 (m, 4H),4.38-4.45 (m, 4H), 6.69 (br d, J = 8.6 Hz, 1H), 6.74-6.77 (m, 1H), 7.02(dd, J = 8.4, 8.2 Hz, 1H), 7.26-7.29 (m, 1H, assumed; partially obscuredby solvent peak), 7.34 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H),9.08 (br s, 1H); 445.0 110

Method A⁵³ 2-{2-[2-(bicyclo[1.1.1]pent-1- yl)-4-chlorophenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.47 min⁴⁹; 465.1, 467.1 120

C54⁵⁴ 7-(4-methyl-1H-imidazol-1- yl)-2-{(2S)-1-[2-pentafluoro-λ⁶-sulfanyl)phenoxy]propan- 2-yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6- dione 1.50 (d, J = 7.0 Hz, 3H), 2.29 (s, 3H),3.75 (ddd, half of ABXY pattern, J = 13.6, 8.0, 4.0 Hz, 1H), 3.86 (ddd,half of ABXY pattern, J = 13.3, 7.0, 3.8 Hz, 1H), 4.15 (dd, J = 9.5, 5.5Hz, 1H), 4.24-4.35 (m, 2H), 4.39 (ddd, half of ABXY pattern, J = 14.6,7.0, 4.0 Hz, 1H), 5.00-5.11 (m, 1H), 7.00-7.10 (m, 2H), 7.14 (br s, 1H),7.27 (d, J = 8.0 Hz, 1H), 7.42-7.51 (m, 2H), 7.76 (br d, J = 8 Hz, 1H),8.23 (br s, 1H); 505.0 121

P1⁵⁵ 7-(4-methyl-1H-imidazol-1- yl)-2-{2-[2-(trimethylsilyl)phenoxy]ethyl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.74 minutes⁴⁹; 437.2 122

Method A; P2⁵⁶ 2-(2-{4-fluoro-2-[2- (trifluoromethyl)oxetan-2-yl]phenoxy}ethyl)-7-(4- methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione, trifluoroacetate salt 2.38minutes⁴⁹; 507.2 123

Example 120; P14⁵⁷ 7-(4-methyl-1H-imidazol-1-yl)-2-{3-[2-(pentafluoro-λ⁶- sulfanyl)phenoxy]butan-2-yl}-3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione ¹H NMR (400 MHz, CD₃OD),mixture of diastereomers at the two methyl groups: δ 1.27-1.35 and1.41-1.50 (2 m, total 6H), 2.24 (br s, 3H), 3.76- 3.94 (m, 2H),4.15-4.25 (m, 1H), 4.32-4.43 (m, 1H), 4.88-5.06 (m, 2H), 7.03-7.11 (m,1H), 7.25- 7.40 (m, 3H), 7.50-7.60 (m, 1H), 7.75-7.82 (m, 2H), 8.34 (brs, 1H); 519.6 124

Example 123⁵⁸ 7-(4-methyl-1H-imidazol-1- yl)-2-{3-[2-(pentafluoro-λ⁶-sulfanyl)phenoxy]butan-2-yl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.01 minutes⁵⁹; 519.3 125

Example 123⁵⁸ 7-(4-methyl-1H-imidazol-1- yl)-2-{3-[2-(pentafluoro-λ⁶-sulfanyl)phenoxy]butan-2-yl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 2.78 minutes⁵⁹; 519.8 126

Example 123⁵⁸ 7-(4-methyl-1H-imidazol-1- yl)-2-{3-[2-(pentafluoro-λ⁶-sulfanyl)phenoxy]butan-2-yl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 7.02 minutes⁶⁰; 519.2 127

Example 123⁵⁸ 7-(4-methyl-1H-imidazol-1-yl)-2- {3-[2-(pentafluoro-λ⁶-sulfanyl)phenoxy]butan-2-yl}- 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 9.19 minutes⁶⁰; 519.2 ¹Potassium hydroxide-mediatedreaction of ethyl 2-bromo-2-methylpropanoate with 2,3-dichlorophenolprovided ethyl 2-(2,3-dichlorophenoxy)-2-methylpropanoate. Afterreduction to the corresponding aldehyde with diisobutylaluminum hydride,reductive amination with 2-aminoethanol provided the requisite2-aminoethanol derivative. ²Ethyl2-[4-(trifluoromethyl)phenoxy]propanoate (D-i. Kato et al., J. Org.Chem. 2003, 68, 7234-7242) was subjected to ammonolysis to provide2-[4-(trifluoromethyl)phenoxy]propanamide. Lithium aluminum hydridereduction gave the corresponding amine, which was converted to therequisite 2-aminoethanol derivative according to Preparation 4.³4-Hydroxy-2,3-dihydro-1H-inden-1-one (W. Liu et al., Org. Lett. 2007,9, 2915-2918) was reduced with sodium cyanoborohydride/trimethylsilylchloride to provide 2,3-dihydro-1H-inden-4-ol. This was chlorinated withN-chlorosuccinimide to generate 7-chloro-2,3-dihydro-1H-inden-4-ol.⁴2-Fluoro-5-methoxybenzaldehyde was subjected to a Baeyer-Villigerreaction, followed by basic ester hydrolysis. The resulting phenol wasreacted with 2-bromo-1,1-dimethoxyethane and potassium carbonate toprovide 2-(2,2-dimethoxyethoxy)-1-fluoro-4-methoxybenzene. Cyclizationwas effected with Amberlyst 15 (see A. Goel and M. Dixit, Synlett 2004,1990-1994) to afford 7-fluoro-4-methoxy-1-benzofuran, which wasdemethylated using boron tribromide. ⁵2-Bromo-1-ethoxy-4-fluorobenzenewas coupled with cyclopropylmagnesium bromide under[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalysis.The resulting 2-cyclopropyl-1-ethoxy-4-fluorobenzene was converted tothe phenol with boron trichloride. ⁶The requisite (2-bromoethoxy)benzenewas prepared via Mitsunobu reaction of 2-bromoethanol with theappropriate phenol. ⁷2-Chloro-4-fluoro-1-methoxybenzene was treated withn-butyllithium and hexachloroethane; the resulting2,3-dichloro-1-fluoro-4-methoxybenzene was demethylated with borontribromide to provide the requisite phenol. ⁸The requsiste phenol may beprepared either from 1-(2-methoxyphenyl)ethanone by the method of Y-i.Lin et al., J. Org. Chem. 1980, 45, 4857-60, or from1-ethynyl-2-methoxybenzene according to L. Shen et al., Bioorg. Med.Chem. 2008, 16, 3321-3341. ⁹Benzyl 2-bromophenyl ether was metalatedwith n-butyllithium and reacted with cyclobutanone; hydrogenation of theresulting 1-[2-(benzyloxy)phenyl]cyclobutanol afforded the requisitephenol. ¹⁰The requisite phenol was prepared as described by D. A. Shultzet al., J. Org. Chem. 2006, 71, 9104-9113.¹¹[2,4-Bis(trifluoromethyl)phenyl]boronic acid was oxidized withhydrogen peroxide to provide the requisite phenol.¹²4-Fluoro-3-(trifluoromethyl)phenol was chlorinated with thionylchloride to afford 2-chloro-4-fluoro-3-(trifluoromethyl)phenol.¹³2-Methyl-4H-chromen-4-one was reacted with Lawesson's reagent, and theproduct was treated with 1,1′-sulfinimidoyldibenzene to provide2-(4-methyl-1,2-thiazol-5-yl)phenol. ¹⁴The appropriately substituted4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione was reacted withhydroxylamine, and the resulting oxime was cyclized under acidicconditions to yield the corresponding3-(2-methoxyphenyl)-5-(trifluoromethyl)isoxazole. Demethylation withboron trichloride provided the requisite phenol. ¹⁵See J. C. Lee et al.,Synth. Commun. 2003, 33, 1611-1614 for the construction of a similar1,3-oxazole. ¹⁶6-Chloro-4H-chromen-4-one was treated with hydroxylaminehydrochloride in ethanol to provide a separable mixture of4-chloro-2-isoxazol-3-ylphenol and 4-chloro-2-isoxazol-5-ylphenol.¹⁷4-Chloro-2-(2-hydroxypropan-2-yl)phenol may be synthesized viareaction of methyl 5-chloro-2-hydroxybenzoate with a methyl Grignardreagent. ¹⁸1-Chloro-2-fluoro-4-methoxybenzene was converted to1-chloro-2-fluoro-3-iodo-4-methoxybenzene (see G. L. Gunewald et al., J.Med. Chem. 1986, 29, 1972-1982).1-Chloro-2-fluoro-3-iodo-4-methoxybenzene was treated with methyldifluoro(fluorosulfonyl)acetate in the presence of copper iodide (A.Khilevich et al., U.S. Pat. Appl. Publ. 2010, US 20100016373) to provide1-chloro-2-fluoro-4-methoxy-3-(trifluoromethyl)benzene.4-Chloro-3-fluoro-2-(trifluoromethyl)phenol was then obtained bydemethylation using boron trichloride.¹⁹(5-Fluoro-2-hydroxyphenyl)boronic acid and4-iodo-2-(trifluoromethyl)pyridine were reacted under Suzuki conditionsto produce 4-fluoro-2-[2-(trifluoromethyl)pyridin-4-yl]phenol. ²⁰Amixture of 4-chloro-2-iodophenol and 3-(trifluoromethyl)-1H-pyrazole wastreated with copper oxide, cesium carbonate and 2-hydroxybenzaldehydeoxime to produce 4-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol.²¹Substituted 2-[5-(trifluoromethyl)-1H-pyrazol-3-yl]phenols may beprepared by sodium hydride-mediated reaction of the appropriate1-(2-methoxyphenyl)ethanone with ethyl trifluoroacetate, followed bycyclization with hydrazine and deprotection of the aryl methyl ether.See S. X. Cao et al., PCT Int. Appl. 2007, WO 2007061923 A2 20070531.²²Alkylation of 4-fluoro-2-(trifluoromethyl)phenol with 1-chloroacetoneafforded 1-[4-fluoro-2-(trifluoromethyl)phenoxy]acetone, which wassubjected to reductive amination with 2-aminoethanol.²³4-Fluoro-2-methylaniline was converted to the diazonium salt andreduced with tin(II) chloride to provide(4-fluoro-2-methylphenyl)hydrazine; this was condensed with ethyl4,4,4-trifluoro-3-oxobutanoate to afford2-(4-fluoro-2-methylphenyl)-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one.²⁴A mixture of the appropriate aniline and ethyl4,4,4-trifluoro-3-oxobutanoate may be treated with polyphosphoric acidto afford the requisite 2-(trifluoromethyl)quinolin-4-ol (see BritishPat. Appl. GB 1419789 A 19751231). ²⁵5-Fluoro-6-methoxynaphthalen-1-olmay be prepared according to J. Liu et al., Bioorg. Med. Chem. Lett.2001, 11, 2903-2905.²⁶2′-Hydroxy-3-(trifluoromethyl)biphenyl-4-carbonitrile was prepared bythe method of J. A. Van Camp et al., Bioorg. Med. Chem. Lett. 2007, 17,5529-5532. ²⁷Iodination of 2-chloro-1-fluoro-4-methoxybenzene (see R.Sanz et al., J. Org. Chem. 2007, 72, 5113-5118) followed by acopper-mediated coupling with methyl difluoro(fluorosulfonyl)acetate anddemethylation with boron trichloride produced3-chloro-4-fluoro-2-(trifluoromethyl)phenol. ²⁸The appropriatelysubstituted isoquinolin-1-ol was treated with N-chlorosuccinimide toprovide the 4-chloroisoquinolin-1-ol, which was treated with phosphorusoxychloride to afford a 1,4-dichloroisoquinoline. This was treated with2-aminoethanol followed by reductive amination of{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde. Deprotection under acidicconditions yielded the requisite2-{{2-[(4-chloroisoquinolin-1-yl)oxy]ethyl}amino)ethanol.²⁹Demethylation of (3-methoxyphenyl)(4-methoxyphenyl)methanone withpyridine hydrochloride followed by monoprotection provided3-(4-hydroxybenzoyl)phenyl 2,2-dimethylpropanoate. Alkylation with5-chloro-1-pentyne followed by basic hydrolysis gave(3-hydroxyphenyl)[4-(pent-4-yn-1-yloxy)phenyl]methanone, which wasconverted to the substituted 2-aminoethanol according to the method ofPreparation 8. ³⁰9H-Carbazol-4-ol was O-protected using benzyl bromide,then N-methylated with iodomethane. Palladium-mediated deprotectionprovided 9-methyl-9H-carbazol-4-ol. ³¹A mixture of1-benzofuran-2-carbaldehyde and propanedioic acid was treated withpiperidine to give (2E)-3-(1-benzofuran-2-yl)prop-2-enoic acid. Theresulting acid was converted to the acyl azide, then cyclized to[1]benzofuro[3,2-c]pyridin-1(2H)-one with tri-n-butylamine at 180° C.Treatment with phosphorus oxychloride provided1-chloro[1]benzofuro[3,2-c]pyridine, which was converted to therequisite 2-aminoethanol according to the method of footnote 32.³²Base-mediated aryl substitution of2-bromo-5-fluoro-3-[2-(trifluoromethyl)-1,3-thiazol-4-yl]pyridine with2-aminoethanol followed by reductive amination of{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde and deprotection underacidic conditions produced2-{[2-{{[5-fluoro-3-[2-(trifluoromethyl)-1,3-thiazol-4-yl]pyridin-2-yl}oxy)ethyl]amino}ethanol.³³Dibenzo[b,d]thiophene-1-ol may be prepared by the method M. M.Oliveira et al, Tetrahedron 2002, 58, 1709-1718.³⁴5-Fluoro-2-methoxyaniline was converted to2,2,2-trifluoro-N-(5-fluoro-2-methoxyphenyl)ethanethioamide viatreatment with trifluoroacetic anhydride followed by Lawesson's reagent.After cyclization to7-fluoro-4-methoxy-2-(trifluoromethyl)-1,3-benzothiazole using themethod of K. Inamoto et al., Org. Lett. 2008, 10, 5147-5150, methylether cleavage with boron trichloride afforded the requisite phenol.³⁵Copper-mediated coupling between the appropriately substituted bromoor iodo methoxybenzene and 3-(trifluoromethyl)-1H-pyrazole yielded amethoxyphenyl-substituted 3-(trifluoromethyl)-1H-pyrazole, which wasdemethylated with boron tribromide to produce the requisite[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol. ³⁶1-Chloroisoquinolin-4-olwas treated with tert-butyldimethylsilyl chloride to product4-{[tert-butyl(dimethyl)silyl]oxy}-1-chloroisoquinoline. Halogenexchange gave 4-{[tert-butyl(dimethyl)silyl]oxy}-1-iodoisoquinoline,which was treated with copper iodide and methyldifluoro(fluorosulfonyl)acetate to produce1-(trifluoromethyl)isoquinolin-4-ol. ³⁷3-Chloro-4-fluorophenol wasacylated with diethylcarbamoyl chloride to produce3-chloro-4-fluorophenyl diethylcarbamate, which was converted to3-chloro-4-fluoro-2-iodophenyl diethylcarbamate via ortho-metalationfollowed by treatment with iodine. Basic hydrolysis provided3-chloro-4-fluoro-2-iodophenol, which was coupled to(2-hydroxyphenyl)boronic acid under Suzuki conditions to give6-chloro-5-fluorobiphenyl-2,2′-diol. Copper-mediated cyclizationprovided 4-fluorodibenzo[b,d]furan-1-ol.³⁸1,2-Dibromo-4,5-difluorobenzene was treated with n-butylithiumfollowed by furan to give 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene,which was treated with acid to produce 6,7-difluoronaphthalen-1-ol.³⁹7-Fluoronaphthalen-1-ol was methylated to give7-fluoro-1-methoxynaphthalene, which was brominated withN-bromosuccinimide to give 1-bromo-6-fluoro-4-methoxynaphthalene.Treatment with n-butyllithium andN-fluoro-N-(phenylsulfonyl)benzenesulfonamide, followed by demethylationwith boron tribromide, afforded 4,7-difluoronaphthalen-1-ol.⁴⁰O-Alkylation of the appropriately substituted phenol with1-bromobutan-2-one, followed by reductive amination with 2-aminoethanol,afforded the requisite 2-aminoethanol derivative.⁴¹[4-(Benzyloxy)-1-(tert-butoxycarbonyl)-1H-indol-2-yl]boronic acid andtrimethyl(trifluoromethyl)silane were combined to give tert-butyl4-(benzyloxy)-2-(trifluoromethyl)-1H-indole-1-carboxylate, which wasdebenzylated via ammonium formate transfer hydrogenation to givetert-butyl 4-hydroxy-2-(trifluoromethyl)-1H-indole-1-carboxylate.⁴²4-(Benzyloxy)-1-methyl-1H-indole and3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole were treated withcopper(I) acetate to give4-(benzyloxy)-1-methyl-2-(trifluoromethyl)-1H-indole. Debenzylation viatransfer hydrogenation with ammonium formate afforded1-methyl-2-(trifluoromethyl)-1H-indol-4-ol. ⁴³A Suzuki reaction between(2-hydroxyphenyl)boronic acid and5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole provided the requisitephenol. ⁴⁴1-(5-Fluoro-2-methoxyphenyl)ethanone was converted to4-fluoro-2-(2,2,2-trifluoro-1,1-dimethylethyl)phenol using the generalmethod of R. M. Garbaccio et al., ACS Med. Chem. Lett. 2010, 1, 406-410.Cleavage of the methyl ether was carried out with boron tribromide toafford the requisite phenol. ⁴⁵Reaction of 2-methoxyphenylmagnesiumbromide with [1.1.1]propellane (see A. B. Shtarev et al., J. Am. Chem.Soc. 2001, 123, 3484-3492) afforded1-(2-methoxyphenyl)bicyclo[1.1.1]pentane, which was treated with borontribromide to provide the requisite phenol. ⁴⁶tert-Butyl[(1S)-2-hydroxy-1-methylethyl]carbamate was O-acylated with benzoylchloride, and the resulting compound was deprotected under acidicconditions. The resulting primary amine was converted to 2-aminoethanolderivative (2S)-2-[(2-hydroxyethyl)amino]propyl benzoate using thegeneral procedure described in Preparation 4. Reaction with P1 under theconditions of Example 1 provided(2S)-2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]propylbenzoate, which was subjected to ester hydrolysis under basic conditionsfollowed by Mitsunobu reaction with 4-chloro-2-(trifluoromethyl)phenol.⁴⁷4-Bromo-1,3-dihydro-2H-inden-2-one was converted to4-bromo-2,2-difluoroindane with (diethylamino)sulfur trifluoride.Palladium-catalyzed reaction with bis(pinacolato)diboron, followed byoxidation with peracetic acid, afforded 2,2-difluoroindan-4-ol.⁴⁸Treatment of (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid withhydrogen peroxide provided 2,2-difluoro-1,3-benzodioxol-4-ol. ⁴⁹HPLCconditions. Column: Waters Atlantis dC18 4.6 × 50 mm, 5 μm; Mobile phaseA: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95% B over4.0 minutes, linear; Flow rate: 2 mL/minute. ⁵⁰HPLC conditions. Column:Waters Acquity HSS T3 2.1 × 50 mm, 1.8 μm; Mobile phase A: 0.05%trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 98% B over1.6 minutes, linear; Flow rate: 1.3 mL/minute. ⁵¹HPLC conditions.Column: Waters XBridge C18 4.6 × 50 mm, 5 μm; Mobile phase A: 0.03%ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammoniumhydroxide in acetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes,linear; Flow rate: 2 mL/minute. ⁵²HPLC conditions. Column: Water XBridgeC18 2.1 × 50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid inwate r(v/v); Mobile phase B: 0.01875% trifluoroacetic acid inactonitrile (v/v); Gradient: 1% to 5% B over 0.6 minutes, then 5% to100% B over 3.4 minutes; Flow rate: 0.8 mL/minute.⁵³2-(Bicyclo[1.1.1]pent-1-yl)phenol (see footnote 45) was chlorinatedaccording to the method of N. Narender et al., Synth. Commun. 2002, 32,279-286 to provide the requisite2-(bicyclo[1.1.1]pent-1-yl)-4-chlorophenol. ⁵⁴Reaction of C54 with1-fluoro-2-(pentafluoro-λ⁶-sulfanyl)benzene was carried out using sodiumhydride. ⁵⁵P1 was converted to2-(2-hydroxyethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionevia reaction with2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethanol according tothe method described for preparation of P8 in Preparation 8, followed byprotecting group removal with hydrogen chloride in methanol.2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)amino]ethanol wassynthesized via reductive amination of{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde with 2-aminoethanol andsodium borohydride. Mitsunobu reaction of2-(2-hydroxyethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionewith 2-(trimethylsilyl)phenol using the method described by T. Tsunodaet al., Tetrahedron Lett. 1993, 34, 1639-1642 afforded this Example.⁵⁶Synthesis of the requisite4-fluoro-2-[2-(trifluoromethyl)oxetan-2-yl]phenol may be carried outfrom 4-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (see J. Zhang etal., Synth. Commun. 2011, 41, 3045-3052). Selective alkylation of thephanol, using allyl bromide and a base such as potassium carbonate,followed by a Swern oxidation of the benzylic alcohol, provides2,2,2-trifluoro-1-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]ethanone. Thismaterial was reacted with trimethylsulfoxonium iodide and potassiumtert-butoxide to afford2-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]-2-(trifluoromethyl)oxetane; theallyl group was removed using tetrakis(triphenylphosphine)palladium(0)and morpholine. ⁵⁷Intermediate2-(3-hydroxybutan-2-yl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dionewas prepared from P14 using the method described for synthesis of C54 inExample 119, except that 3-aminobutan-2-ol was used in place of(2S)-2-aminopropan-1-ol. Example 123 is a mixture of four diastereomers,which were separated to provide Examples 124-127. ⁵⁸Example 123 wasseparated into its diastereomers (Examples 124-127) via the followingsequence: Example 123 was subjected to HPLC separation (Column:Phenomenex Silica, 5 μm; Mobile phase A: heptane; Mobile phase B:ethanol; Gradient: 5% to 100% B) to afford a mixture of the two higherR_(f) compounds (Mixture A) and a mixture of the two lower R_(f)compounds (Mixture B). Mixture A was separated via supercritical fluidchromatography (Column: Chiralpak AS-H, 5 μm; Mobile phase: 75:25 carbondioxide/ethanol). Example 124 was the first-eluting isomer, and thesecond-eluting isomer was Example 125. Mixture B was separated viasupercritical fluid chromatography (Column: Chiralpak AS-H, 5 μm; Mobilephase: 80:20 carbon dioxide/methanol, containing 0.2% isopropylamine).Example 126 was the first-eluting isomer, and second-eluting isomer wasExample 127. ⁵⁹Supercritical fluid chromatography conditions. Column:Chiralpak AS-H, 4.6 × 250 mm, 5 μm; Mobile phase: 80:20 carbondioxide/ethanol; Flow rate: 2.5 mL/minute. ⁶⁰Supercritical fluidchromatography conditions. Column: Chiralpak AS-H, 4.6 × 250 mm, 5 μm;Mobile phase: 75:25 carbon dioxide/methanol; Flow rate: 2.5 mL/minute.

TABLE 2 ¹H NMR (400 MHz, CDCl₃), δ (ppm); Mass spectrum, observed Methodof ion m/z (M + 1) Preparation; or HPLC retention Non- time (minutes);commercial Mass spectrum Ex Starting m/z (M + 1) (unless # StructureMaterials IUPAC Name otherwise indicated) 111

Ex 1 2-{2-[4-chloro-2- (trifluoromethyl) phenoxy]ethyl}-8-(4-methyl-1H-imidazol- 1-yl)-2,3,4,5- tetrahydropyrido[1,2-a][1,4]diazepine-1,7- dione 2.51 min³; 481.1, 483.1 112

Ex 1¹ (4S)-2-{2-[4-fluoro-2- (trifluoromethyl) phenoxy]ethyl}- 4-methyl-7-(4-methyl-1H- imidazol-1-yl)-3,4- dihydro-2H- pyrido[1,2-a]pyrazine-1,6-dione 1.43 (d, J = 6.6 Hz, 3H), 2.29 (br s, 3H), 3.67(dd, J = 13.6, 1.4 Hz, 1H), 3.89-3.96 (m, 1H), 4.08-4.16 (m, 2H), 4.32(br dd, J = 4.7, 4.6 Hz, 2H), 5.23-5.30 (m, 1H), 6.95 (dd, J = 9.0, 4.2Hz, 1H), 7.15 (br s, 1H), 7.19- 7.25 (m, 1H), 7.27 (d, J = 7.7 Hz, 1H),7.33 (dd, J = 8.0, 3.1 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 8.25 (br s,1H); 465.2 113

Ex 1; P11² 7-(4-chloro-1H- imidazol-1-yl)-2{2-[4- chloro-2-(trifluoromethyl) phenoxy]ethyl}-3,4- dihydro-2H- pyrido[1,2-a]pyrazine-1,6-dione 3.14 min³; 487.1, 489.1// ¹H NMR (400 MHz, CD₃OD) δ3.89- 3.94 (m, 2H), 4.01 (dd, J = 5.1, 5.0 Hz, 2H), 4.31-4.38 (m, 4H),7.22 (br d, J = 9.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.54-7.58 (m,2H), 7.60 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.26 (d, J =1.6 Hz, 1H) 114

Ex 1; P11 7-(4-chloro-1H- imidazol-1-yl)-2-{2-[2- (trifluoromethyl)phenoxy]ethyl}-3,4- dihydro-2H- pyrido[1,2- a]pyrazine-1,6-dione 2.89min³; 452.9, 454.9 115

Ex 1; P10, C41 2-{2-[(7- fluoronaphthalen-1- yl)oxy]ethyl}-7-(2-methylpyridin-4-yl)- 3,4-dihydro-2H- pyrido[1,2- a]pyrazine-1,6-dione2.38 min³; 444.0 116

Ex 1; P10² 2-{2-[4-chloro-2- (trifluoromethyl) phenoxy]ethyl}-7-(2-methylpyridin-4-yl)- 3,4-dihydro-2H- pyrido[1,2- a]pyrazine-1,6-dione2.61 (br s, 3H), 3.90-3.95 (m, 2H), 3.98-4.03 (m, 2H), 4.29-4.38 (m,4H), 6.93 (br d, J = 8.8 Hz, 1H), 7.24-7.28 (m, 1H, assumed; partiallyobscured by solvent peak), 7.43 (br d, J = 5 Hz, 1H), 7.48 (br d, J = 9Hz, 1H), 7.54- 7.59 (m, 2H), 7.68 (d, J = 7.2 Hz, 1H), 8.55 (br d, J = 5Hz, 1H); 478.1 ¹(2R)-1-Aminopropan-2-ol was used in place of2-aminoethanol. ²See Example 22 for preparation of the requisite2-aminoethanol. ³HPLC conditions: see footnote 49 in Table 1.

ADDITIONAL EXAMPLES

Additional compounds within the scope of this invention, such as thoselisted below, may be prepared by one of ordinary skill in the art, usingthe methods illustrated in these Examples, either alone or incombination with techniques generally known in the art.

2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(3-chloro-1H-1,2,4-triazol-1-yl)-2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-7-(3-methylisothiazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-7-(2-methyl-1,3-thiazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-chloro-2-(trifluoromethyl)phenoxy]ethyl}-7-(3-methylisoxazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{4-fluoro-2-[1-(trifluoromethyl)cyclopropyl]phenoxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{4-fluoro-2-[1-(trifluoromethyl)cyclopropyl]phenoxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[2-(2,2-difluoro-1-methylcyclopropyl)-4-fluorophenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-fluoro-2-(trimethylsilyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[2-(2,2-difluorocyclopropyl)-4-fluorophenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-2-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[5-fluoro-8-methyl-8-(trifluoromethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[2-(2,2-difluoro-1-methylcyclopropyl)-4-fluorophenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-fluoro-2-(trimethylsilyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[2-(2,2-difluorocyclopropyl)-4-fluorophenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-2-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[5-fluoro-8-methyl-8-(trifluoromethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-2-methyl-2-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-2-methyl-2-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-3-methyl-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{[7-fluoro-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{[7-fluoro-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-4-yl]oxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[2-(2-bicyclo[1.1.1]pent-1-yl-4-chlorophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[2-(2-bicyclo[1.1.1]pent-1-yl-4-fluorophenoxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-(2-bicyclo[1.1.1]pent-1-yl-4-chlorophenoxy)-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-(2-bicyclo[1.1.1]pent-1-yl-4-fluorophenoxy)-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-chloro-2-(3-fluorobicyclo[1.1.1]pent-1-yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-fluoro-2-(3-fluorobicyclo[1.1.1]pent-1-yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-chloro-2-(3-fluorobicyclo[1.1.1]pent-1-yl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-fluoro-2-(3-fluorobicyclo[1.1.1]pent-1-yl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-(2-{4-fluoro-2-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]phenoxy}ethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-[(1S)-2-{4-fluoro-2-[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]phenoxy}-1-methylethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,7-trifluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,7-trifluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-fluoro-2-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[4-fluoro-2-(2,2,2-trifluoro-1-methylethyl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(7-chloro-2,2-difluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,8-trifluoro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,5-trifluoro-3,4-dihydro-2H-chromen-8-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,5-trifluoro-2H-chromen-8-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(4,4,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(3,3,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,7-trifluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,7-trifluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1-benzofuran-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-fluoro-2-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[4-fluoro-2-(2,2,2-trifluoro-1-methylethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(7-chloro-2,2-difluoro-2,3-dihydro-1H-inden-4-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,8-trifluoro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,5-trifluoro-3,4-dihydro-2H-chromen-8-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,5-trifluoro-2H-chromen-8-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(4,4,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(3,3,8-trifluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(3,3,7-trifluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(3,3-difluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-2H-chromen-5-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-3,4-dihydro-2H-chromen-8-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-2H-chromen-8-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(4,4-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(3,3-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(4,4-difluoro-4H-chromen-5-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(8,8-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(4,8,8-trifluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(7,7-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(3,3,7-trifluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(3,3-difluoro-2,3-dihydro-1H-inden-4-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-4-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-2H-chromen-5-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-3,4-dihydro-2H-chromen-8-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-2H-chromen-8-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(4,4-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(3,3-difluoro-3,4-dihydro-2H-chromen-5-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(4,4-difluoro-4H-chromen-5-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(8,8-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(4,8,8-trifluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(7,7-difluoro-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-methyl-2-[(2,2,4-trifluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{(1S)-2-[(2,2-difluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

7-(4-methyl-1H-imidazol-1-yl)-2-{2-[(2,2,4-trifluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

2-{2-[(2,2-difluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;

pentafluoro(5-fluoro-2-{2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]ethoxy}phenyl)sulfur;

pentafluoro[5-fluoro-2-({(2S)-2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]propyl}oxy)phenyl]sulfur;

pentafluoro(2-{2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]ethoxy}phenyl)sulfur;and

pentafluoro[2-({(2S)-2-[7-(4-methyl-1H-imidazol-1-yl)-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-2-yl]propyl}oxy)phenyl]sulfur.

Cell-Based v-Secretase Assay with ELISA Readout

The ability of compounds to modulate production of amyloid beta proteinAβ(1-42) was determined using human WT-APP overexpressing CHO cells.Cells were plated at 22,000 cells/100 μL well in 96 well tissue culturetreated, clear plates (Falcon) in DMEM/F12 based medium and incubatedfor 24 hours at 37° C. Compounds for testing were diluted in 100% DMSOto achieve an eleven points, half log, dose response for IC₅₀determinations. Compounds were added in fresh medium to achieve 1% finalDMSO. Appropriate vehicle or inhibitor controls were added into controlwells individually to obtain minimum or maximum inhibition values,respectively, for the assay signal window before the plates wereincubated for ˜24 hours at 37° C. This procedure produces conditionedmedia in each well which is tested for Aβ(1-42) levels in the ELISAdetection step described next. The remaining cell cultures in each wellare also tested for cell toxicity as described below.

Coating of ELISA assay plates was initiated by addition of 50 μL/well ofan in-house Aβ(1-42) specific antibody at (3 μg/mL) in 0.1 M NaHCO₃ (pH9.0) into black 384-well Maxisorp® plates (Nunc) and incubated overnightat 4° C. The capture antibody was then aspirated from the ELISA assayplates and plates were washed 4×100 μL with Wash Buffer (Dulbecco's PBS,0.05% Tween 20). 90 μL/well of Blocking Buffer (Dulbecco's PBS, 1.0% BSA(Sigma A7030)) was then added to plates. Ambient temperature incubationwas allowed to proceed for a minimum of two hours. Blocking buffer wasthen removed and 20 μL/well Assay Buffer (Dulbecco's PBS, 1.0% BSA(Sigma A7030), 0.05% Tween 20) was then added. At this point, 40 μL (induplicate) of experimental conditioned media (described above) weretransferred into wells of the blocked ELISA plates containing thecapture antibody, followed by overnight incubation at 4° C. Celltoxicity was also measured in the corresponding remaining cells afterremoval of the conditioned media for the Aβ(1-42) assay by acolorimetric cell proliferation assay (CellTiter 96®AQ_(ueous) OneSolution Cell Proliferation Assay, Promega) according to themanufacturer's instructions.

After overnight incubation of the ELISA assay plates at 4° C., unboundAβ peptides were removed via (4×100 μL) washes with Wash Buffer.Europium (Eu) labeled (custom labeled, Perkin Elmer) Aβ(1-16) 6e10Monoclonal Antibody (Covance #SIG-39320) was added, (50 μL/well Eu-6e10@ 1:10,000, 20 uM EDTA) in Assay Buffer. Incubation at ambienttemperature for a minimum of 2 hours was followed by (4×100 μL) washeswith Wash Buffer, before 30 μL/well of Delfia Enhancement Solution(Perkin Elmer) was added. Following an one hour ambient temperatureincubation, the plates were read on an EnVision plate reader (PerkinElmer) using standard DELFIA TRF settings. Data analysis includinginhibitory IC₅₀ determination was performed using nonlinear regressionfit analysis (in-house software) and the appropriate plate mean valuesfor the maximum and minimum inhibition

TABLE 3 Aβ 42B IC₅₀ (nM) Example (Geometric Mean of number 2-6Determinations) 1  256^(a) 2 434 3  86 4 146 5 996 6   36.5 7   42^(b) 8 93 9   83.9 10 127 11 536 12 196 13 108 14  197^(b) 15 275 16 234 17153 18  151^(b) 19 203 20 157 21 262 22  103^(a) 23 173 24  104^(b) 25  73.2 26   95.7 27 103 28   31.9 29  154^(b) 30 132 31    96.8^(b) 32143 33 194 34 262 35 133 36 302 37 219 38 293 39 525 40   19.6 41 156 42   5.31 43 283 44 142 45   66.3 46    9.38 47    9.48 48 143 49 178 50  29.3 51  20 52   23.5 53   26.2 54 215 55 168 56 399 57 113 58   72.159  530^(b) 60   33.3 61 108 62   39.7 63    76.6^(b) 64   42.4 65  46.1 66    52.4^(b) 67   58.4 68   59.4 69   58.3 70 135 71    4.22 72  14.8 73   43.7 74   38.5 75    62.3^(b) 76   58.6 77   66.2 78   87.5^(b) 79    7.23 80 152 81 384 82 209 83   12.3 84   71.5 85 10686 107 87   22.8 88   75.4 89 101 90 147 91 120 92    4.87 93   75.8^(b) 94 108 95 143 96   48.2 97   21.3 98   19.4 99   25.3 100135 101 456 102   33.7 103  596^(b) 104    7.2 105    25.2^(b) 106  27.4 107   34.4 108   46.8 109 275 110   14.5 111 138 112 340 113 292114 1320^(b) 115 489 116 3490^(b) 117    3.54 118    <6.64^(c) 119   7.49 120   17.8 121   30.2 122   85.6 123 106 124 2310^(b) 125 653126   20.1 127 1070^(b) ^(a)IC₅₀ value represents the geometric meanof >15 determinations. ^(b)IC₅₀ value is from a single determination.^(c)IC₅₀ value represents the geometric mean of 7-15 determinations.

We claim:
 1. A compound having the structure of Formula I:

wherein: X is a 5- to 14-membered heteroaryl containing 1-3 heteroatoms;R¹ is hydrogen, halogen, or C₁₋₆alkyl; wherein said alkyl may beoptionally and independently substituted with one to three of fluoro,cyano, —CF₃, hydroxyl, or C₁₋₆alkoxy groups; R^(2a) and R^(2b) for eachoccurrence are each independently hydrogen, fluoro, cyano, —CF₃, orC₁₋₆alkyl; wherein said alkyl may be optionally and independentlysubstituted with cyano, C₁₋₃alkyl or one to three fluoro; R³ is—(C(R¹¹)₂)_(t)—(C₆₋₁₀aryl); wherein said aryl may be optionally andindependently substituted with one to five R¹⁰; R^(4a) and R^(4b) areeach independently hydrogen, —CF₃, or C₁₋₆alkyl, wherein said alkyl isoptionally substituted with one to three —CF₃, cyano or fluoro; R^(5a)and R^(5b) for each occurrence are each independently hydrogen, —CF₃, orC₁₋₆alkyl, wherein said alkyl is optionally substituted with one tothree —CF₃, cyano or fluoro; R⁶and R⁷ are each independently hydrogen,—CF₃, cyano, halogen, C₁₋₆alkyl or —OR⁹; provided that R⁶ and R⁷ cannotboth be —OH; R⁹ is hydrogen, or C₁₋₆alkyl, wherein said alkyl may beoptionally and independently substituted with cyano, or one to threefluoro; each R¹⁰ is independently hydrogen, halogen, cyano, —CF₃,C₁₋₆alkyl, —(C(R¹¹)₂)_(m)—OR¹², —C(O)R¹³, —SF₅ or —Si(CH₃)₃; whereinsaid alkyl, may be optionally and independently substituted with one tothree R¹⁴; each R¹¹ is independently hydrogen, C₁₋₆alkyl, fluoro, —CF₃,—CHF₂ or —OR¹²; wherein said alkyl may be optionally independentlysubstituted with one to three fluoro or cyano; each R¹² is independentlyhydrogen, C₁₋₆alkyl, or —CF₃; wherein said alkyl may be optionallyindependently substituted with one to three R¹⁶; each R¹³ isindependently C₁₋₆alkyl; wherein said alkyl may be optionally andindependently substituted with one to three R¹⁶; each R¹⁴ isindependently hydrogen, C₁₋₆alkyl, halogen, cyano, —CF₃, —CHF₂, —OR⁹ or—OCF₃; R¹⁶ is independently hydrogen, —CF₃, cyano, halogen, C₁₋₆alkyl or—OR⁹ and t and m are each an integer independently selected from 0, 1,2, 3 and 4; z is the integer 1; y is an integer selected from 1, 2, 3and 4; or a pharmaceutically acceptable salts thereof.
 2. The compoundaccording to claim 1 wherein X is imidazolyl, pyrazolyl, isothiazolyl,thiazolyl, isoxazolyl, oxazolyl or pyridyl.
 3. The compound according toclaim 2 wherein X is imidazolyl.
 4. The compound according to claim 3wherein R¹ is C₁₋₆alkyl.
 5. The compound according to claim 4 wherein R¹is methyl optionally substituted with one hydroxyl or C₁₋₆alkoxy or oneto three fluoro; and y is two or three.
 6. The compound according toclaim 5 wherein R¹⁰ is independently hydrogen, halogen, cyano, —CF₃,C₁₋₆alkyl, —(C(R¹¹)₂)_(m)—OR¹² or —C(O)R¹³; wherein the alkyl may beindependently substituted with one to three R¹⁴.
 7. The compoundaccording to claim 5 wherein R³ is phenyl.
 8. The compound according toclaim 7 wherein R¹⁰ is hydrogen, chloro, fluoro, bromo, cyano, —CF₃,—OCF₃, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hydroxyl, ormethoxy.
 9. The compound according to claim 8 wherein R^(2a) and R^(2b)are hydrogen or C₁₋₆alkyl.
 10. A compound selected from the groupconsisting of:2-{(1S)-2-[4-fluoro-2-(trifluoromethyl)phenoxy]-1-methylethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-{2-[4-fluoro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;2-{(2S)-1-[4-chloro-2-(trifluoromethyl)phenoxy]propan-2-yl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;or a pharmaceutically acceptable salt of any of the above.
 11. A methodfor treating a mammal having Alzheimer's Disease comprisingadministering to the mammal a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable vehicle, diluent or carrier.